WO2022261029A2 - Peptide nucleic acid therapeutics for trinucleotide repeat disorders - Google Patents

Peptide nucleic acid therapeutics for trinucleotide repeat disorders Download PDF

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WO2022261029A2
WO2022261029A2 PCT/US2022/032402 US2022032402W WO2022261029A2 WO 2022261029 A2 WO2022261029 A2 WO 2022261029A2 US 2022032402 W US2022032402 W US 2022032402W WO 2022261029 A2 WO2022261029 A2 WO 2022261029A2
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compound
group
unit
alkyl
independently
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PCT/US2022/032402
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WO2022261029A3 (en
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Dietrich A. Stephan
Ramesh U. BATWAL
Barry BADEAU
William R. Mann
Austin KILGORE
Dani STOLTZFUS
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Neubase Therapeutics, Inc.
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Priority to CA3173359A priority Critical patent/CA3173359A1/en
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Publication of WO2022261029A3 publication Critical patent/WO2022261029A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C07K14/003—Peptide-nucleic acids (PNAs)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
    • C12N2310/3181—Peptide nucleic acid, PNA
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/333—Modified A
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide

Definitions

  • Hereditary disorders are characterized by genetic abnormalities that can range from a single base mutation in a single gene to the addition or deletion of an entire chromosome or set of chromosomes.
  • One such hereditary disorder is Huntington’s disease, a neurodegenerative disorder caused by a single defective gene on chromosome 4.
  • the present disclosure provides a compound comprising:
  • oligomeric sequence comprises a repeating unit of formula: ionized form thereof, wherein:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group;
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the present disclosure provides a compound comprising a structure that is: N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-£- wherein: the number of units with variables defined independently is at least 11;
  • A-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently methyl substituted with a heterocycle;
  • C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a gene associated with a neurodegenerative disease phenotype.
  • the present disclosure provides a compound comprising an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
  • FIG. 1 Panel A illustrates relative HTT protein expression in mice treated with Compound 76 or vehicle.
  • FIG. 1 Panel B illustrates a schematic of transcription engagement by PNA binding to mutant HTT mRNA.
  • FIG. 2 Panel A illustrates relative HTT protein expression in mice treated with Compound 77 or vehicle.
  • FIG. 2 Panel B illustrates a schematic of genome engagement by PNA binding to mutant HTT DNA.
  • FIG. 3 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
  • R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
  • FIG. 4 illustrates the structure of Compound 1.
  • FIG. 5 illustrates the structure of Compound 2.
  • FIG. 6 illustrates the structure of Compound 16.
  • FIG. 7 illustrates the structure of Compound 52.
  • FIG. 8 illustrates the structure of Compound 57.
  • FIG. 9 illustrates the structure of Compound 58.
  • FIG. 10 illustrates the structure of Compound 59.
  • FIG. 11 illustrates the structure of Compound 75.
  • FIG. 12 illustrates the structure of Compound 76.
  • FIG. 13 illustrates the structure of Compound 77.
  • HD Huntington’s disease
  • AD is a progressive neurodegenerative disorder associated with cognitive impairment, dementia, and loss of motor coordination. While the disease primarily manifests in the brain, HD can be considered a whole-body disease. Conditions associated with HD include weight loss, muscle atrophy, glucose intolerance, osteoporosis, testicular atrophy, heart failure, and/or cardiac abnormalities.
  • HD associated with a defective gene the Huntingtin (HTT) gene, on chromosome 4.
  • HTT Huntingtin
  • mHTT abnormal mutant protein
  • the progressive and heritable increase in length of CAG repeats encode a polyglutamine tract in the coding region of the HTT gene.
  • CAG repeats can increase in number from one generation to another.
  • the normal allele of the HTT gene can comprise fewer than 36 CAG repeats, whereas the mutant allele can comprise more than 36 repeats.
  • HTT normal or wild type HTT is widely expressed and important for cell signaling, transcriptional regulation, molecular trafficking, and axonal transport, modulating brain-derived neurotrophic factor (BDNF) production.
  • BDNF brain-derived neurotrophic factor
  • Aberrant accumulation of CAG repeats can confer a toxic gain-of-function phenotype, causing the protein to aggregate and form protein deposits (inclusion bodies).
  • Neuronal loss can start in the striatum and progress to the cortex.
  • Disease severity generally reflects the extent of expanded repeats in the mutant HTT protein.
  • compounds, compositions, and methods for the treatment of HD can, for example, reduce or inhibit expression of the disease-causing HTT gene by targeting nucleic acids associated with the mutant HTT expression, e.g., RNA or DNA precursors of mutant HTT.
  • the compounds can bind to nucleic acid molecule associated with HD, thereby reducing mRNA expression or protein expression of the disease- causing HTT gene.
  • compositions thereof that reduce expression of the disease-causing HTT gene and compositions thereof.
  • Non-limiting examples of compounds of the disclosure are provided in TABLE 1.
  • Residue structures, pendant nucleobase identities (when present), and monomer chemical names associated with the symbols used in the structure codes of TABLE 1 and TABLE 2 are provided in TABLE 3.
  • Compounds can be provided as a pharmaceutically-acceptable salt, tautomer, or ionized form thereof.
  • A L-alanine
  • R L.-arginine
  • N L- sparagine
  • D L--aspartic acid
  • C L-cysteine
  • E L-glutamic acid
  • Q L-glutamine
  • G glycine
  • H L-histidine
  • I L-isoleucine
  • L L- leucine
  • K L-lysine
  • M L-methionine
  • F L-phenylalanine
  • P L-proline
  • S L-serine
  • T L- threonine
  • W L-tryptophan
  • Y L-tyrosine
  • V L-valine.
  • C(&) represents an L-cysteine residue that is covalently bound via the sulfur atom of its side chain to a sulfur atom of another L-cysteine residue represented by C(&).
  • a compound having the sequence code GC(&)GGGGGC(&)G comprises two cysteine residues that are bound to each other via an intrachain disulfide bond.
  • a chemical name is provided for the corresponding unincorporated monomer.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guani dinoalkyl.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
  • the structure is a peptide nucleic acid structure.
  • the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG) n (SEQ ID NO: 135) or (CTG) n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guanidinoalkyl.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG) n (SEQ ID NO: 135) or (CTG) n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guani dinoalkyl.
  • the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG) n (SEQ ID NO: 135) or (CTG) n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH. wherein the structure binds to the sequence of nucleic acids at the subsequence that is (CAG) n (SEQ ID NO: 135) or (CTG) n (SEQ ID NO: 182).
  • the sequence of nucleic acids is a DNA sequence. In some embodiments, the sequence of nucleic acids is a DNA sequence, and the subsequence is (CTG) n (SEQ ID NO: 182). In some embodiments, the sequence of nucleic acids is a RNA (e.g., mRNA) sequence. In some embodiments, the sequence of nucleic acids is a RNA (e.g., mRNA) sequence, and the subsequence is (CAG) n (SEQ ID NO: 135).
  • the disclosure provides a composition comprising a compound that is therapeutically-effective for treatment of a neurodegenerative disease, wherein the compound comprises a structure that is:
  • C-Terminus is OH, OMe, or NH 2 ;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent
  • L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • PEP1 is absent. In some embodiments, PEP1 is the peptide sequence. In some embodiments, the peptide sequence of PEP 1 is a nuclear localization sequence. In some embodiments, PEP1 is a sequence that is -(//-Arg)-(//-Arg)-(/J-Arg)-(/J- Arg)- (SEQ ID NO: 181). In some embodiments, PEP1 is a sequence that is -Tyr-Gly-Arg-Lys- Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149).
  • PEP1 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148). In some embodiments, PEP1 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141). In some embodiments, PEP1 is -Cys'-Leu-Ser-Ser-Arg-Leu-Asp-Ala-Cys 2 - , wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142).
  • PEP1 is a sequence that is -Cys 1 -Ala-Gly-Ala-Leu-Cys 2 -Tyr-, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143). In some embodiments, PEP1 is a sequence that is -Cys'-Leu-Glu-Val-Ser-Arg-Lys-Asn-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144).
  • PEP1 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82). In some embodiments, PEP1 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145).
  • PEP1 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146). In some embodiments, PEP1 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
  • PEP2 is absent. In some embodiments, PEP2 is the peptide sequence. In some embodiments, the peptide sequence of PEP2 is a nuclear localization sequence. In some embodiments, PEP2 is a sequence that is -(I)-Arg)-(1)-Arg)-(1)-Arg)-(1)- Arg)- (SEQ ID NO: 181). In some embodiments, PEP2 is a sequence that is -Tyr-Gly-Arg-Lys- Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149).
  • PEP2 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148). In some embodiments, PEP2 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141). In some embodiments, PEP2 is -Cys'-Leu-Ser-Ser-Arg-Leu-Asp-Ala-Cys 2 - , wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142).
  • PEP2 is a sequence that is -Cys 1 -Ala-Gly-Ala-Leu-Cys 2 -Tyr-, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143). In some embodiments, PEP2 is a sequence that is -Cys'-Leu-Glu-Val-Ser-Arg-Lys-Asn-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144).
  • PEP2 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82). In some embodiments, PEP2 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145).
  • PEP2 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146). In some embodiments, PEP2 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
  • SOL1 is absent. In some embodiments, SOL1 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL1 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL1 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-. [0039] In some embodiments, the water-solubilizing group of SOL1 is a group of formula: , wherein
  • R la is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOL1 is a group of formula: wherein p is an integer that is 1-1,000.
  • p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7.
  • the water-solubilizing group of SOL1 is a group of formula:
  • R lb is H, alkyl, or a nitrogen atom protecting group
  • R 2b is O, NH, N(alkyl), or N(Pg N1 ), wherein Pg N1 is a nitrogen atom protecting group; R ’b is H, alkyl, or a nitrogen atom protecting group;
  • R 4b is H, alkyl, or a nitrogen atom protecting group
  • R 5b is alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 5b groups in the structure are independently methyl substituted with a heterocycle;
  • J is O, NH, N(alkyl), or N(Pg N1 ); z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and v is an integer that is 1-1,000.
  • the water-solubilizing group of SOL1 is a group of formula: wherein v is an integer that is 1-1000.
  • v is an integer that is 1-100. In some embodiments, v is an integer that is 1-50. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, v is an integer that is 3, 4, 5, 6, or 7. In some embodiments, v is an integer that is 6.
  • SOL2 is absent.
  • SOL2 is the water- solubilizing group.
  • the water-solubilizing group of SOL2 is a peptide sequence.
  • the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH.
  • the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH.
  • the water- solubilizing group of SOL2 is a polyethyleneglycol group.
  • the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH 2 ) 2 C(0)-Arg-Arg-. [0046]
  • the water-solubilizing group of SOL2 is a group of formula: , wherein
  • R la is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • the water-solubilizing group of SOL2 is a group of formula: wherein p is an integer that is 1-1,000.
  • p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7.
  • the water-solubilizing group of SOL2 is a group of formula:
  • R lb is H, alkyl, or a nitrogen atom protecting group
  • R 2b is O, NH, N(alkyl), or N(Pg N1 ), wherein Pg N1 is a nitrogen atom protecting group; R ’b is H, alkyl, or a nitrogen atom protecting group;
  • R 4b is H, alkyl, or a nitrogen atom protecting group
  • R 5b is alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 5b groups in the structure are independently methyl substituted with a heterocycle;
  • J is O, NH, N(alkyl), or N(Pg N1 ); z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and v is an integer that is 1-1,000.
  • the water-solubilizing group of SOL2 is a group of formula: wherein v is an integer that is 1-1000.
  • v is an integer that is 1-100. In some embodiments, v is an integer that is 1-50. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, v is an integer that is 3, 4, 5, 6, or 7. In some embodiments, v is an integer that is 6.
  • PNA1 is the peptide nucleic acid sequence.
  • PNA2 is the peptide nucleic acid sequence.
  • L1 is the linker group. In some embodiments, the linker group of L1 is cleavable. In some embodiments, the linker group of L1 is non-cleavable. In some embodiments, the linker group of L1 is a peptide sequence. In some embodiments, the linker group of L1 is a polyamine sequence. In some embodiments, the linker group of L1 is a polyamide sequence. In some embodiments, the linker group of L1 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid.
  • the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L1 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L1 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L1 is -Lys-NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)- In some embodiments, the linker group of L1 is -Lys-NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L1 is -Arg-NH(CH 2 ) 5 C(0)-.
  • the linker group of L1 is -NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L1 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L1 is -NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • the linker group of L1 is -NH(CH 2 ) 5 C(O)NH(Ctl 2 ) 2 -(/I-arginine)-(7J-arginine)- (D)-arginine). In some embodiments, the linker group of L1 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L1 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L1 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 O) 2 CH 2 C(0)-.
  • the linker group of L1 is - NN(CH 2 CH 2 O) 2 CH 2 C(O-) NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L1 is - NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group of L1 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L1 is a peptide sequence that is -Lys-.
  • L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid.
  • the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is -NHCH(C00H)C(CH3) 2 S-SC(CH3) 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L2 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-.
  • the linker group ofL2 is -Lys-NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L2 is -Lys-NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L2 is -NH(CH 2 ) 5 C(O)-.
  • the linker group of L2 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L2 is -NH(CH 2 ) 5 C(O)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0). In some embodiments, the linker group of L2 is -NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 -(/I-arginine)-(yJ-arginine)- (D -arginine).
  • the linker group of L2 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L2 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L2 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-.
  • the linker group of L2 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)- NH(CH 2 CH 2 O) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L2 is - NH(CH 2 CH 2 O) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group ofL2 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L2 is a peptide sequence that is -Lys-.
  • L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid.
  • the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L3 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group ofL3 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3) 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L3 is -Lys-NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L3 is -Arg-NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L3 is -NH(CH 2 ) 5 C(0)-.
  • the linker group of L3 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L3 is -NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0). In some embodiments, the linker group of L3 is -M I(CI I ) ⁇ C(0)NI I(CI I;)>-(/J-arginine)-(7J-arginine)- (D-arginine).
  • the linker group of L3 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L3 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L3 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L3 is -MIlGLhCbhO ⁇ CbhCXO)- NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-.
  • the linker group of L3 is - NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group ofL3 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L3 is a peptide sequence that is -Lys-.
  • L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid.
  • the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(1SIH 2 )C(0)-.
  • the linker group of L4 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH 2 )C(0)-. In some embodiments, the linker group of L4 is NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-Lys-. In some embodiments, the linker group of L4 is NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(1SIH 2 )C(0)-Lys-. In some embodiments, the linker group of L4 is -Arg-NH(CH2)5C(0)-.
  • the linker group of L4 is -NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L4 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)MI(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L4 is -NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • the linker group of L4 is -MI(CH 2 ) 5 C(0)NH(CH 2 ) 2 -(//-arginine)-(/J-arginine)- (77-arginine). In some embodiments, the linker group of L4 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L4 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L4 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-.
  • the linker group of L4 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)- NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L4 is - NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group ofL4 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L4 is a peptide sequence that is -Lys-.
  • L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid.
  • the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L5 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group ofL5 is NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-Lys-. In some embodiments, the linker group of L5 is NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-Lys-. In some embodiments, the linker group of L5 is -Arg-NH(CH 2 ) 5 C(0)-.
  • the linker group of L5 is -NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L5 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L5 is -NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • the linker group of L5 is -NH(CH 2 ) 5 C(0)NH(Ctl 2 ) 2 -(//-arginine)-(7J-arginine)- (Z)-arginine). In some embodiments, the linker group of L5 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L5 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L5 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-.
  • the linker group of L5 is -NHlGhhChkO ⁇ ChhClO)- NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L5 is - NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group of L5 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L5 is a peptide sequence that is -Lys-.
  • L6 is the linker group. In some embodiments, the linker group of L6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid.
  • the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-.
  • the linker group of L6 is -NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-. In some embodiments, the linker group of L6 is NHCH(C00H)C(CH 3 ) 2 S-SC(CH 3 ) 2 CH(NH 2 )C(0)-Lys-. In some embodiments, the linker group of L6 is NHCH(C00H)C(CH 3 ) 2 S-SCH 2 CH(NH 2 )C(0)-Lys-. In some embodiments, the linker group of L6 is -Arg-NH(CH 3 ) 2 C(0)-.
  • the linker group of L6 is -NH(CH 2 ) 5 C(0)-. In some embodiments, the linker group of L6 is - NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 C(0)-. In some embodiments, the linker group of L6 is -NH(CH 2 ) 5 C(0)-Arg-NH(CH 2 ) 2 C(0)-Arg-NH(CH 2 ) 2 C(0).
  • the linker group of L6 is -NH(CH 2 ) 5 C(0)NH(CH 2 ) 2 -(/9-arginine)-(/9-arginine)- (79-arginine). In some embodiments, the linker group of L6 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-. In some embodiments, the linker group of L6 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L6 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-.
  • the linker group of L6 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)- NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L6 is - NH(CH 2 CH 2 0) 2 CH 2 C(0)-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-Arg-. In some embodiments, the linker group ofL6 is -NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-NH(CH 2 CH 2 0) 2 CH 2 C(0)-Arg-. In some embodiments, the linker group of L6 is a peptide sequence that is -Lys-.
  • the structure is: wherein: the number of units with variables defined independently is at least 11;
  • A-Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; and
  • C-Terminus is OH, OMe, NH 2 , or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the structure is:
  • the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype. In some embodiments, the structure binds to a mRNA sequence transcribed from a gene associated with a neurodegenerative disease phenotype by interactions between the heterocycles of the R 2 groups and nucleobases of the gene. In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease (HD) phenotype. In some embodiments, the HD gene is a non-wild type HD gene. In some embodiments, the non-wild type HD gene differs from a wild type HD gene in a repeat expansion mutation.
  • HD Huntington’s disease
  • the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG) n (SEQ ID NO: 135) or (CTG) n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1-20, an integer from 1-15, or an integer from 1-10.
  • the structure binds to the mRNA sequence at the subsequence that is (CAG) n (SEQ ID NO: 135).
  • the structure binds to the DNA sequence at the subsequence that is (CTG) n (SEQ ID NO: 182).
  • the number of units with variables defined independently is 11- 1,000. In some embodiments, the number of units with variables defined independently is 11- 100. In some embodiments, the number of units with variables defined independently is 11-50. In some embodiments, the number of units with variables defined independently is 11, 12, 13,
  • each R 1 is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2- yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent-l-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl. In some embodiments, each R 1 is independently alkyl that is substituted.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1- hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4-aminobut-l-yl, 3-aminoprop-l-yl, 1- H-imidazoM-ylmethyl, I -H-indol-3-ylmethyl, benzyl, 4-hydroxyphen-l-ylmethyl, 2- carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3 -guani dinoprop- 1-yl, 4-guanidinobut-l-yl, 2- carbamoyleth-l-yl, or 3 -carbarn oylprop- 1-yl.
  • each R 1 is independently H, hydroxylmethyl, or 4-guanidinobut- l-yl. In some embodiments, at least one iteration of R 1 is hydroxylmethyl. In some embodiments, at least a third of the iterations of R 1 are hydroxylmethyl. In some embodiments, at least half the iterations of R 1 are hydroxylmethyl.
  • each R alpha is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop- 1-yl, prop-2- yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent-l-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl.
  • each R alpha is independently alkyl that is substituted.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4-aminobut- 1 -yl, 3- aminoprop-l-yl, 1 -H-imidazol-4-yl methyl, I -H-indol-3-ylmethyl, benzyl, 4-hydroxyphen-l- ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guani dinoprop- 1-yl, 4-guanidinobut- l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R alpha is independently H, 3-guanidinoprop-l-yl, or 4- guanidinobut-l-yl. In some embodiments, at least one iteration of R alpha is 3-guanidinoprop-l-yl. In some embodiments, at least a third of the iterations of R alpha are 3-guanidinoprop-l-yl. In some embodiments, at least half the iterations of R alpha are 3-guanidinoprop-l-yl.
  • the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty- second units, independently if present, are each 3-guanidinoprop-l-yl.
  • At least a third of the R 2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R 2 groups in the structure are methyl substituted with a heterocycle.
  • the heterocycles of the R 2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R 2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R 2 groups are divalent nucleobases.
  • the heterocycles of the R 2 groups are each independently:
  • the heterocycles of the R 2 groups are each independently:
  • the heterocycles of the R 2 groups are each independently:
  • the heterocycles of the R 2 groups are each independently:
  • each R 2 is independently: methyl
  • each R 2 is independently: methyl
  • each R 2 is independently: methyl
  • the heterocycles of the R 2 groups are each independently:
  • the heterocycles of the R 2 groups are each independently:
  • the heterocycles of the R 2 groups are each independently:
  • each R 2 is independently: methyl
  • each R 2 is independently: methyl
  • each R 2 is independently: methyl
  • each R 2 is independently:
  • each R 2 is independently:
  • N -Terminus is H.
  • N-Terminus is acyl.
  • a ' -Terminus is the biological agent.
  • the biological agent is a vitamin E group.
  • the biological agent is an O-bound tocopherol group.
  • C- Terminus is NH 2 .
  • C-Terminus is -Pro-Lys-Lys-Lys-Arg-Lys-Val- NH 2 .
  • the neurodegenerative disease is Huntington's disease.
  • the disclosure provides a compound comprising a structure that is: wherein: the number of units with variables defined independently is at least 11;
  • N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle;
  • C-Terminus is OH, OMe, or NH 2 ;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the structure is: wherein: the number of units with variables defined independently is at least 11; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; and
  • C-Terminus is OH, OMe, NH 2 , or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the disclosure provides a compound comprising a structure that is: wherein: the number of units with variables defined independently is at least 3; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R 1 is a hydroxyalkyl group; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or ME;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent; wherein at least one of PEP 1 and PEP2 is a peptide sequence of at least three amino acid residues,
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the disclosure provides a compound comprising a structure that is: wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero; 77-Terminus is H, acyl, a group that together with the nitrogen atom to which 77-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R 3 is independently a hydroxyalkyl group; each R 4 is independently R 2 ; each R 5 is independently a group that is not hydroxyalkyl; each R 6 is independently R 2 ; each R 7 is independently alkyl that is unsubstituted or substituted or H; each R 8 is independently R 2 , wherein: the first number of units with variables
  • C-Terminus is OH, OMe, or MH
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the first number of units with variables defined independently is 3-1,000. In some embodiments, the first number of units with variables defined independently is 3-100. In some embodiments, the first number of units with variables defined independently is 3-50. In some embodiments, the first number of units with variables defined independently is 3,
  • the first number of units with variables defined independently is at least 11. In some embodiments, the first number of units with variables defined independently is 11-
  • the first number of units with variables defined independently is
  • the first number of units with variables defined independently is 11-50. In some embodiments, the first number of units with variables defined independently is
  • the second number of units with variables defined independently is 3-1,000. In some embodiments, the second number of units with variables defined independently is 3-100. In some embodiments, the second number of units with variables defined independently is 3-50. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
  • the third number of units with variables defined independently is 3-1,000. In some embodiments, the third number of units with variables defined independently is 3-100. In some embodiments, the third number of units with variables defined independently is 3-50. In some embodiments, the third number of units with variables defined independently is
  • the third number of units with variables defined independently is at least 11. In some embodiments, the third number of units with variables defined independently is 11-1,000. In some embodiments, the third number of units with variables defined independently is 11-100. In some embodiments, the third number of units with variables defined independently is 11-50. In some embodiments, the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. [0096] In some embodiments, each R 3 is hydroxymethyl. In some embodiments, each R 5 is H.
  • the disclosure provides a compound comprising a repeating unit of formula: wherein: each R 1 is independently a hydroxyalkyl group; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R 3 is independently a group that is not hydroxy alkyl; each R 4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R alpha1 is independently alkyl that is unsubstituted or substituted or H; and each R alpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
  • the disclosure provides a compound comprising:
  • an oligomeric sequence connected to the region that comprises the structure that interferes with expression of the gene associated with a neurodegenerative disease phenotype, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula: ionized form thereof, wherein:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O- alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O- alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
  • the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
  • the structure binds to a DNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
  • the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R 2 groups and nucleobases of the Huntington’s disease gene.
  • the Huntington’s Disease gene is a non-wild type Huntington’s disease gene.
  • the non-wild type Huntington’s disease gene differs from a wild type Huntington’s disease gene in a repeat expansion mutation.
  • the structure binds to a RNA (e.g., mRNA) sequence that contains a subsequence that is (CAG) n (SEQ ID NO: 135), wherein n is an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1-20, an integer from 1-15, or an integer from 1-10.
  • n is an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1-20, an integer from 1-15, or an integer from 1-10.
  • the structure binds to the mRNA sequence at the subsequence that is (CAG) n (SEQ ID NO: 135).
  • the structure binds to a DNA sequence that contains a subsequence that is (CTG) n (SEQ ID NO: 182), wherein n is an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1- 20, an integer from 1-15, or an integer from 1-10.
  • the structure binds to the DNA sequence at the subsequence that is (CTG) n (SEQ ID NO: 182).
  • the disclosure provides a compound comprising:
  • the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
  • the disclosure provides a compound comprising:
  • R 1 is H, alkyl, or a nitrogen atom protecting group
  • R 2 is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3 is H, alkyl, or a nitrogen atom protecting group
  • R 4 is H, alkyl, or a nitrogen atom protecting group
  • R 5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), orN(Pg N );
  • E 1 is a chemical moiety
  • E 2 is a chemical moiety
  • n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
  • p is an integer that is 1-1,000, or a pharmaceutically-acceptable salt or ionized form thereof.
  • the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
  • the number of units with variables defined independently is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein: a first unit is present or absent, and in the first unit: a second unit is present or absent, and in the second unit: a third unit is present, and in the third unit: a fourth unit is present, and in the fourth unit: a fifth unit is present, and in the fifth unit: a sixth unit is present, and in the sixth unit: a seventh unit is present, and in the seventh unit: an eighth unit is present, and in the eighth unit: a ninth unit is present, and in the ninth unit: a tenth unit is present, and in the tenth unit: an eleventh unit is present, and in the eleventh unit: a twelfth unit is present, and in the twelfth unit: a thirteenth unit is present, and in the thirteenth unit: a fourteenth unit is present, and in the fourteenth unit: a fifteenth unit is present or absent, and in the fifteenth unit
  • R 1 is H or -CH 2 OH; and R 2 i iss a twenty-third unit is present or absent, and in the twenty-third unit: an twenty-fourth unit is present or absent, and in the twenty-fourth unit: a twenty-fifth unit is present or absent, and in the twenty-fifth unit: a twenty-sixth unit is present or absent, and in the twenty-sixth unit: [00107]
  • the units with variables defined independently counting from N -Terminus, the first unit, the fourth unit, the seventh unit, the tenth unit, the thirteenth unit, the sixteenth unit, the nineteenth unit, the twenty-second unit, and the twenty-fifth unit, independently if present, each have
  • the number of units with variables defined independently is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein: a first unit is present or absent, and in the first unit: a second unit is present or absent, and in the second unit: a third unit is present, and in the third unit: a fourth unit is present, and in the fourth unit: a fifth unit is present, and in the fifth unit: a sixth unit is present, and in the sixth unit: a seventh unit is present, and in the seventh unit: an eighth unit is present, and in the eighth unit: a ninth unit is present, and in the ninth unit: a tenth unit is present, and in the tenth unit: an eleventh unit is present, and in the eleventh unit: a twelfth unit is present, and in the twelfth unit: a thirteenth unit is present, and in the thirteenth unit: a fourteenth unit is present, and in the fourteenth unit: a fifteenth unit is present or absent, and in the fifteenth unit
  • the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty -third unit, and the twenty-sixth unit some embodiments, in the second unit, the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty-third unit, and the twenty-sixth unit,
  • R 2 is some embodiments, in the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, and the twenty-fourth unit, R 2 is some embodiments, in the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty-fourth
  • R 1 is hydrogen in each of the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty sixth unit.
  • R 1 is hydrogen.
  • R 1 is -CH2OH.
  • R 1 is -CH2OH.
  • R alpha is -CH2OH.
  • R alpha is -CH 2 OH.
  • R alpha is 3-guanidino- prop-l-yl.
  • R alpha is 3-guanidino-prop-l-yl.
  • R 1 is 4-guanidino-but-l-yl.
  • R 1 is 4-guanidino-but- l-yl.
  • FIG. 4 illustrates the structure of Compound 1.
  • FIG. 5 illustrates the structure of Compound 2.
  • FIG. 6 illustrates the structure of Compound 16.
  • FIG. 7 illustrates the structure of Compound 52.
  • FIG. 8 illustrates the structure of Compound 57.
  • FIG. 9 illustrates the structure of Compound 58.
  • FIG. 10 illustrates the structure of Compound 59.
  • FIG. 11 illustrates the structure of Compound 75.
  • FIG. 12 illustrates the structure of Compound 76.
  • FIG. 13 illustrates the structure of Compound 77.
  • FIG. 3 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen.
  • R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen.
  • One or more oligonucleotide residues of a compound of the disclosure may be independently replaced with a residue comprising an alternative oligonucleotide backbone bearing an identical nucleobase.
  • Nonlimiting examples of oligonucleotide backbones suitable for use in the present disclosure include phosphorothioate deoxyribonucleic acid (PS-DNA), boranophosphate DNA, alpha-, beta- constrained nucleic acid (a, ⁇ -CnA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'- fluororibonucleic acid (2'-F-RNA), 2'-fluoroarabinonucleic acid (2'-F-ANA), sulfonyl-linked nucleic acid, methylene(methylimino) (MMI) linked, formacetal-linked nucleic acid, threose nucleic acid (TNA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'-0-(2- methoxyethyl)ribonucleic acid (2'-MOE-RNA), unlocked nucleic acid (UNA), 2'-0,4'-C- ethylene-bridged
  • a compound of the disclosure can be conjugated to one or more polypeptides, such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake.
  • polypeptides such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake.
  • cell- penetrating peptides include SV40 NLS (SEQ ID NO: 1: PKKKRKV), c-Myc NLS (SEQ ID NO: 2: PAAKRVKLD), nuleoplasmin (SEQ ID NO.
  • LRRERQ SRLRRERQ SR LRRERQ SRLRRERQ SR
  • DPV15b SEQ ID NO: 18: GAYDLRRRERQ SRLRRRERQSR
  • HIV-1 Tat SEQ ID NO: 19: RKKRRQRRR
  • FHV coat SEQ ID NO: 20: RRRRNRTRRNRRRVR
  • HIV-1 Rev SEQ ID NO: 21: TRQARRNRRRRWRERQR
  • HTLV- II Rex SEQ ID NO: 22: TRRQRTRRARRNR
  • BMV Gag SEQ ID NO: 23: KMTRAQRRAAARRNRWTAR, P22 N (SEQ ID NO: 24 NAKTRRHERRRKLAIER), lN(1- 22) (SEQ ID NO: 25: MDAQTRRRERRAEKQAQWKAAN), f21N(12-29) (SEQ ID NO: 26:
  • AKTRYK ARRAEL1AERR T AKTRYK ARRAEL1AERR
  • Yeast Prp6 SEQ ID NO: 27: TRRNKRNRIQEQLNRK
  • Protamine 1 SEQ ID NO: 28: PRRRRS S SRP VRRRRRPRV SRRRRRRGGRRRR
  • Human cJun SEQ ID NO: 29: RIKAERKRMRNRIAASKSRKRKLERIAR
  • Human cFos SEQ ID NO: 30: KRRIRRERNKMAAAKSRNRRRELTDT
  • Yeast GCN4 SEQ ID NO: 31 : KRARNTEAARRSRARKLQRMKQ
  • Penetratin SEQ ID NO: 32:
  • YT AIAW VK AFIRKLRK Pep-1 (SEQ ID NO: 58: KETWWETWWTEWSQPKKRKV), EB-1 (SEQ ID NO: 59: L1RLW SHL1HIWFQNRRLKWKKK), Pyrrho-coricin (SEQ ID NO: 60: VDKGSYLPRPTPPRPIYNRN), 439a (SEQ ID NO: 61: GSPW GLQHHPPRT), MAP (SEQ ID NO: 62: KLALKALKALKAALKLA), Bip (1) (SEQ ID NO: 63: IPALK), Bip (2) (SEQ ID NO: 64: VPALR), pVEC (SEQ ID NO: 65: LL1ILRRRIRKQAHAHSK), YTA4 (SEQ ID NO: 66: IAWVKAFIRKLRKGPLG), K-FGF+NLS (SEQ ID NO: 67:
  • a compound of the disclosure is conjugated to a peptide that targets specific tissue, such as a muscle-targeting peptides.
  • Suitable muscle targeting peptides can include, for example, MSP1 (SEQ ID NO: 77: AKASSLNIA), MSP2 (SEQ ID NO: 78: ASSLNIA), and A2G80 (SEQ ID NO: 79: VQLRNGFPYFSY).
  • a compound of the disclosure is conjugated to a peptide that targets brain tissue.
  • Suitable brain targeting peptides can include, for example, SEQ ID NO: 142: C(&)LS SRLD AC(&), SEQ ID NO: 143: C(&)AGALC(&)Y, SEQ ID NO: 144: C(&)LEVSRKNC(&), SEQ ID NO: 145: C(&)TSTSAPYC(&), SEQ ID NO: 146: c(&)MPRLRGC(&), and SEQ ID NO: 147: T GNYK ALHPHN G.
  • peptides suitable for conjugation with a compound of the disclosure include transferrin receptor binders, such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH), as well as peptides that bind transferrin receptor-transferrin complex, such as CRT (SEQ ID NO: 82: C(&)RTIGPSVC(&)).
  • transferrin receptor binders such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH)
  • CRT SEQ ID NO: 82: C(&)RTIGPSVC(&)
  • Retro-enantio analogues of any peptide disclosed herein are also suitable for conjugation to a compound of the present disclosure.
  • a retro-enantio analogue can mimic the natural function of a corresponding parent peptide while exhibiting increased resistance to degradation.
  • a retro-enantio analogue includes a peptide analogue where, relative to a parent peptide, both the linear peptide sequence and alpha-carbon chirality are inverted.
  • a retro-enantio analogue of THR (SEQ ID NO: 80: THRPPMWSPVWP) can be THRre (SEQ ID NO: 83: pwvpswmpprht), and a retro-enantio analogue of HAI (SEQ ID NO: 81: HAIYPRH) can be HAIre (SEQ ID NO: 84: hrpyiah), where lowercase one letter codes denote D-amino acid residues.
  • Enantiomers of any peptide disclosed herein are also contemplated, which enantiomers can include, for example, D-THR (SEQ ID NO: 85: thrppmwspvwp).
  • peptides suitable for conjugation with a compound of the disclosure include peptides consisting of or comprising sequences such as RFQILYR (SEQ ID NO: 86), RYQFL1R (SEQ ID NO: 87), RIQFL1R (SEQ ID NO: 88), RRWQW (SEQ ID NO: 89), GWWG (SEQ ID NO: 90), GFWFG (SEQ ID NO: 91), and GRKKRRQRRRPQ (SEQ ID NO: 92).
  • sequences such as RFQILYR (SEQ ID NO: 86), RYQFL1R (SEQ ID NO: 87), RIQFL1R (SEQ ID NO: 88), RRWQW (SEQ ID NO: 89), GWWG (SEQ ID NO: 90), GFWFG (SEQ ID NO: 91), and GRKKRRQRRRPQ (SEQ ID NO: 92).
  • Peptides comprising repeating units of charged residues are also contemplated, such as sequences comprising repeating units of contiguous arginine and glycine residues, such as (RG) e where e is from 1 to 50 (SEQ ID NO: 138) (e g. SEQ ID NO: 93: RGRGRGRGRGRGRGRG), polyarginine comprising from 2 to 100 contiguous arginine residues (SEQ ID NO: 139), (e.g. SEQ ID NO:
  • a compound of the disclosure is conjugated to a sequence derived from HIV-1 Tat, which can include, for example, RKKRRQRRR (SEQ ID NO: 19),
  • a compound of the disclosure is complementary to a nucleic acid sequence selected from the group consisting of: CUG, CUGC, CUGCU, CUGCUG,
  • sequence variants of the sequences described herein are contemplated.
  • a variant typically differs from a sequence specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions.
  • Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of sequences of the disclosure and evaluating one or more biological activities of the compounds as described herein.
  • Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid and/or nucleic acid sequences of the compound. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., modulation of a genetic target.
  • Percent (%) sequence identity with respect to a reference polypeptide or oligonucleotide sequence is the percentage of amino acid residues, nucleoside residues, and/or nucleoside analogue residues in a candidate sequence that are identical with residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.
  • Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • the degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs designed for this purpose, such as global or local alignment algorithms.
  • Non-limiting examples include BLAST, BLAST-2, AL1GN, Megalign (DNASTAR), BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LAL1GN, SSEARCH2SEQ, or another suitable method, software or algorithm.
  • a global alignment algorithm such as a Needleman and Wunsch algorithm, can be used to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Default settings can be used.
  • % sequence identity values can be generated using the sequence comparison computer program AL1GN-2.
  • the AL1GN-2 program can be compiled for use on a UNIX operating system, including digital UNIX V4.0D. Sequences that can be compared by these algorithms include, for example, peptides, oligonucleotides, PNAs, and analogues of any of the foregoing.
  • the percent identity determination can be made based on comparison of the nucleobases or amino acid side chains. Residues in the two molecules being compared can be considered to share identity for the purpose of the percent identity analysis if the residues share a common nucleobase or amino acid side chain even if the residues have non-identical backbone structures. For example, Compound 58 and Compound 59 can be considered to share 100% nucleobase sequence identity.
  • Non-proteogenic acids can include, for example, ⁇ -alanine, cystine, cystathionine, lanthionine, t-leucine, norleucine, homonorleucine, ornithine, allothreonine, homocysteine, citrulline, homoserine, isovaline, norvaline, sarcosine, N-ethyl glycine, N-propyl glycine, N-isopropyl glycine, N-methyl alanine, N-ethyl alanine, N-methyl ⁇ -alanine, N-ethyl ⁇ -alanine, and isoserine.
  • modifications described herein can be associated with modifications of one or more amino acids of the compounds.
  • modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N- linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitination, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination.
  • nucleobases within a PNA subunit can be naturally occurring or non-naturally occurring.
  • Non-limiting examples of nucleobases include adenine, guanine, thymine, cytosine, uracil, pseudoisocytosine, 2-thiopseudoisocytosine, 5-methylcytosine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine (or 2,6-diaminopurine), 2-thiouracil, 2-thiothymine, 2- thiocytosine, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-chlorocytosine,5-bromocytosine, 5- iodocytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 7-methylguanine, 7-methyladenine,
  • Compounds disclosed herein can comprise divalent nucleobases.
  • a divalent nucleobase can simultaneously bind specifically to two nucleic acid strands, whether or not the two strands are independent strands, two portions of a single strand (e.g., in a hairpin), or contain mismatches in the sense that at one or more positions within the two strands at the site of binding to the genetic recognition reagents, the bases are not able to base pair according to traditional Watson-Crick base pairing (A-T/U, T/U-A, G-C or C-G).
  • Divalent nucleobases can be incorporated into an oligonucleotide analogue backbone such as those described in FIG. 3 (e.g.
  • PNA monomer which can then be incorporated into an oligomer of monomers with a desired sequence of nucleobases.
  • TABLE 4 provides example divalent bases and their binding specificities, where R 1 is hydrogen or a nitrogen protecting group and X is N or CH.
  • Compounds described herein can comprise Attorney Docket No. 54344-731.601 one or more isotopic substitutions.
  • hydrogen can be in any isotopic form, including X H (protium), 2 H (D or deuterium), and 3 H (T or tritium).
  • Carbon can be in any isotopic form, including 12 C, 13 C, and 14 C.
  • Oxygen can be in any isotopic form, including 16 O and 18 O.
  • Compounds described herein can comprise one or more asymmetric centers, and can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods including chiral high-performance liquid chromatography (HPLC), selective crystallization as chiral salts, or in the presence of chiral hosts, or from chiral solvents, and through enrichment using enzymes or chemical processes such as dynamic kinetic resolution.
  • HPLC high-performance liquid chromatography
  • a single isomer can be prepared by asymmetric synthesis.
  • the disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.
  • Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups.
  • An alkyl group can be, for example, a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , c 46 , C 47 , C 48 , C 49 , or C 50 group that is substituted
  • Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
  • Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, secbutyl, and t-butyl.
  • Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include
  • a cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
  • alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups.
  • the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
  • An alkenyl or alkenylene group can be, for example, a C2, C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
  • Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups.
  • the triple bond of an alkylnyl or alkynylene group can be internal or terminal.
  • An alkylnyl or alkynylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47
  • a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
  • a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
  • a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
  • An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
  • An ether or an ether group comprises an alkoxy group.
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
  • An aryl group can be heterocyclic or non-heterocyclic.
  • An aryl group can be monocyclic or polycyclic.
  • An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
  • Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
  • An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.
  • An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.
  • An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.
  • a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
  • a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
  • a heterocycle can be aromatic -69- Attorney Docket No.54344-731.601 (heteroaryl) or non-aromatic.
  • Non-limiting examples of heterocycles include nucleobases, pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
  • An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle.
  • Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl.
  • An acyloxy group can be an oxygen atom substituted with an acyl group.
  • An ester or an ester group comprises an acyloxy group.
  • a non-limiting example of an acyloxy group, or an ester group, is acetate.
  • a carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle.
  • a hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and can include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups.
  • a hydrocaryl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C 19 , C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 group.
  • a hydrocarbylcarbonyl group can be a carbonyl group substituted with a hydrocarbyl group, which can be, for example, benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undencanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, l
  • a hydrocarylcarbonyl group can be, for example, a C 2 , C 3 , C 4 , C 5 , C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C 19 , C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C 49 , or C 50 group.
  • An aminoalkylene group can be an alkyl group substituted with an amino group, such as, for example, aminomethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1-yl, 4- aminopent-1-yl, 3-aminopent-1-yl, 2-aminopent-1-yl, a lysine side chain, or an ornithine side chain.
  • amino group such as, for example, aminomethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1-yl, 4- aminopent-1-
  • a guanidinoalkylene group can be an alkyl group substituted with a guanidino group, -70- such as, for example, guanidinomethyl, 2-guanidinoeth-l-yl, 3-guanidinoprop-l-yl, 2- guanidinoprop-1-yl, 4-guanidinobut-l-yl, 3-guanidinobut-l-yl, 2-guanidinobut-l-yl, 5- guanidinopenty-1-1, 4-guanidinopent-l-yl, 4-guanidinopent-l-yl, 3-guanidinopent-l-yl, 2- guanidinopent-l-yl, an arginine side chain, or a homoarginine side chain.
  • a guanidino group such as, for example, guanidinomethyl, 2-guanidinoeth-l-yl, 3-guanidinoprop-l-yl, 2- guanidinoprop-1-
  • Polypeptides and proteins disclosed herein can comprise synthetic amino acids in place of one or more naturally-occurring amino acids.
  • Such synthetic amino acids can include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl- cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4- chlorophenylalanine, 4-carboxyphenylalanine, ⁇ -phenylserine ⁇ -hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2, 3, 4-tetrahydroisoquinoline-3 -carboxylic acid, aminomalonic acid, aminomalonic acid
  • a compound of a disclosure bears one or more nitrogen protecting groups.
  • nitrogen protecting groups include methyl, formyl, ethyl, acetyl, anisyl, benzyl, benzoyl, carbamate, trif!uoroacetyl.
  • compositions provide the use of pharmaceutically-acceptable salts of any therapeutic compound described herein.
  • Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically- acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, A-methylpiperidine, A-ethyl pi peri dine. dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.
  • an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an A f -m ethyl m orphol i ne salt, a piperidine salt, an A-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the present disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benz
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a trifluoroacetate salt, a mandelate salt, a cinnamate salt, an aspartate salt, a stearate salt, a palmitate salt, a glycolate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 4
  • Compounds, compositions, and methods of the disclosure can be used to treat a condition in a subject in need thereof, for example, a repeat expansion disorder, such as trinucleotide repeat expansion disorder.
  • the methods can comprise administering to a subject in need thereof a therapeutically-effective amount of a compound disclosed herein.
  • a condition to be treated can be a repeat expansion disorder, such as a trinucleotide repeat expansion disorder.
  • the repeat can be present, for example, in a 5' UTR, an intron, an exon, or a 3 r UTR of a gene.
  • a trinucleotide repeat expansion disorder can be a disorder that involves an expansion of a CAG repeat (a polyglutamine disease).
  • Non-limiting examples of disorders that comprise an expansion of a CAG repeat include HD (Huntington's disease), with a repeat expansion in the HTT gene, DRPLA (Dentatorubropallidoluysian atrophy), with a repeat expansion in the ATN1 gene, SBMA (Spinal and bulbar muscular atrophy), with a repeat expansion in the AR gene, SCA1 (Spinocerebellar ataxia Type 1), with a repeat expansion in the ATXN1 gene, SCA2 (Spinocerebellar ataxia Type 2), with a repeat expansion in the ATXN2 gene, SCA3 (Spinocerebellar ataxia Type 3), with a repeat expansion in the ATXN3 gene, SCA6 (Spinocerebellar ataxia Type 6), with a repeat expansion in the CACNA1 A gene, SCA7 (Spinocerebellar ataxia Type 7), with a repeat expansion in the ATXN7 gene, SCA12 (Spinocerebellar
  • a pharmaceutical composition, compound, or method of the disclosure is used for treating an animal model of Huntington’s disease (HD), such as an zQ175KI mouse model of HD.
  • HD Huntington’s disease
  • a composition, compound, or method of the disclosure is used for treating HD.
  • a composition, compound, or method of the disclosure is used for treating spinocerebellar ataxia type 1.
  • SBMA Spinal and bulbar muscular atrophy.
  • a composition, compound, or method of the disclosure is used for treating DRPLA (Dentatorubropallidoluysian atrophy).
  • a composition, compound, or method of the disclosure is used for treating a polyglutamine (PolyQ) disease.
  • a composition, compound, or method of the disclosure is used for treating SCA1 (Spinocerebellar ataxia Type 1).
  • a composition, compound, or method of the disclosure is used for treating SCA2 (Spinocerebellar ataxia Type 2).
  • a composition, compound, or method of the disclosure is used for treating SCA3 (Spinocerebellar ataxia Type 3).
  • a composition, compound, or method of the disclosure is used for treating SCA6 (Spinocerebellar ataxia Type 6).
  • a composition, compound, or method of the disclosure is used for treating SCA7 (Spinocerebellar ataxia Type 7). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA12 (Spinocerebellar ataxia Type 12). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA17 (Spinocerebellar ataxia Type 17).
  • a condition to be treated is a neurological condition.
  • the condition is a neurodegenerative condition.
  • a condition to be treated is a neuromuscular condition.
  • the condition is a central nervous system condition and/or a peripheral nervous system condition.
  • the condition is a multisystem degenerative disorder.
  • a condition to be treated is a muscular dystrophy.
  • the condition is associated with aging.
  • the condition comprises or is associated with cognitive impairment or intellectual disability.
  • the condition comprises or is associated with depression.
  • the condition comprises or is associated with tremor.
  • the condition comprises or is associated with deterioration of motor skills.
  • the condition comprises or is associated with impaired glucose tolerance. In some embodiments, the condition comprises or is associated with weight loss. In some embodiments, the condition comprises or is associated with progressive muscle wasting and/or weakness. In some embodiments, the condition comprises or is associated with cataract development. In some embodiments, the condition comprises or is associated with reduced lifespan. In some embodiments, the condition comprises or is associated with myotonia (sustained muscle contraction, e.g., an inability to relax muscles at will). In some embodiments, the condition comprises or is associated with cardiac pathology, such as cardiac conduction abnormalities. In some embodiments, the condition comprises or is associated with arrhythmia. In some embodiments, the condition is a congenital condition. In some embodiments, the condition comprises or is associated with hypotonia.
  • the condition comprises or is associated with severe generalized weakness. In some embodiments, the condition comprises or is associated with respiratory insufficiency. In some embodiments, the condition comprises or is associated with chorea. In some embodiments, the condition comprises or is associated with a hyperkinetic movement disorder. In some embodiments, the condition comprises or is associated with dementia.
  • the condition is a genetic disorder. In some embodiments, the condition is an autosomal dominant genetic disorder. In some embodiments, the condition comprises or is associated with mis-splicing of gene transcripts. In some embodiments, the condition comprises or is associated with altered protein products that are dysfunctional as a result of mis-splicing. In some embodiments, the condition comprises or is associated with sequestration of splice regulators. In some embodiments, the condition comprises or is associated with aggregation of mRNA in the nucleus. In some embodiments, the severity of the condition is associated with the number of trinucleotide repeats in a trinucleotide repeat expansion. In some embodiments, the condition is a monogenic disorder, e.g., comprises or is associated with an inherited defect in a single gene.
  • the condition is Huntington’s disease. In some embodiments, the condition is juvenile Huntington’s disease. In some embodiments, the condition is adult-onset Huntington’s disease.
  • the disclosure provides a method of treating Huntington’s disease, the method comprising contacting a cell of a subject (e.g., patient) suffering from Huntington’s disease with a compound disclosed herein. Upon contacting a compound disclosed herein with the cell, the compound can penetrate the cell membrane, endosome, and nucleus, engage mutant HTT (mHTT) mRNA, and knock down mHTT expression.
  • the disclosure provides a method of treating an animal model of HD, the method comprising contacting a cell of a subject (e.g., zQ175KI heterozygous mouse) with a compound disclosed herein. Upon contacting a compound disclosed herein with the cell, the compound can penetrate the cell membrane, endosome, and nucleus, engage mHTT mRNA, and knock down mHTT expression.
  • a compound or composition of the disclosure can be administered on the basis of the number of CAG repeats in a gene, for example, in the ATN1 gene, HTT gene, AR gene,
  • the efficacy of a compound, composition, or method of the disclosure can vary based on the number of CAG repeats in a gene, for example, in the ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene.
  • the number of CAG repeats in a gene can be variable in the general population, for example, the number of CAG repeats in HD can be in a range of about 6 to about 35 repeats in subjects that do not have HD.
  • the number of CAG repeats in subjects with HD can be at least 36 and in some cases upwards of 100.
  • the efficacy of a compound, composition, or method of the disclosure can vary based on the number of repeats in the gene or locus.
  • a compound or composition is administered to a subject or contacted to a cell having a gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene) that comprises at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, or at least about 120 CAG repeats.
  • the gene is HD.
  • the gene is not HD. In some embodiments, the gene is Atrophin 1 (ATN1). In some embodiments, the gene is not ATN1. In some embodiments, the gene is Huntingtin (HTT). In some embodiments, the gene is not HTT. In some embodiments, the gene is Androgen receptor (AR). In some embodiments, the gene is not AR. In some embodiments, the gene is Ataxin 1 (ATXN1). In some embodiments, the gene not ATXN1. In some embodiments, the gene is Ataxin 2 (ATXN2). In some embodiments, the gene not ATXN2. In some embodiments, the gene is Ataxin 3 (ATXN3). In some embodiments, the gene not ATXN3.
  • ATN1 Atrophin 1
  • HTT Huntingtin
  • AR Androgen receptor
  • the gene is not AR.
  • the gene is Ataxin 1 (ATXN1). In some embodiments, the gene not ATXN1. In some embodiments, the gene is Ataxin 2 (ATXN2). In some embodiment
  • the gene is Ataxin 7 (ATXN7). In some embodiments, the gene not ATXN7. In some embodiments, the gene is CACNA1A. In some embodiments, the gene is not CACNA1A. In some embodiments, the gene is PPP2R2B. In some embodiments, the gene is not PPP2R2B. In some embodiments, the gene is TATA-binding protein (TBP). In some embodiments, the gene is not TBP. In some embodiments the gene is HTT that has at most about 30, at most about 35, at most about 40, at most about 50, at most about 60, at most about 80, or at most about 100 trinucleotide repeats.
  • a trinucleotide repeat expansion comprises at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about
  • the trinucleotide repeat expansion has at most about 40, at most about 50, at most about 60, at most about 70, at most about 80, at most about 90, or at most about 100 trinucleotide repeats.
  • a cell, population of cells, or subject that does not have a trinucleotide repeat expansion contains at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 36, at most 37, at most 38, at most 39, at most 40, at most 41, at most 42, at most 43, at most 44, at most 45, at most 50, at most 60, at most 70, at most 80, at most 90, at most 100, at most 110, at most 120, at most 130, at most 140, at most 150, at most 200, or at most 250 copies of the trinucleotide (e.g., CAG) in the repeat region of the gene (e g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1A gene, ATXN7 gene, PPP2R2B gene, or TBP gene).
  • the trinucleotide e.g., CAG
  • the disclosure provides a method of treating a nucleotide repeat expansion disorder in a subject, comprising administering a compound disclosed herein to the subject.
  • the nucleotide repeat expansion disorder comprises expression of CAG-repeat-containing mRNA by the subject.
  • the subject is a mammal.
  • the subject is human.
  • the subject is a mouse.
  • a compound or composition is administered to a subject or contacted to a cell having a gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene) that comprises at least about 30, least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 250, at least about 300, at least about 350, at least about 400, at least about 450, at least about 500, at least about 600, at least about 700, at least about 800, at least about
  • a repeat expansion comprises at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about
  • the repeat expansion has at most about 100, at most about 250, at most about 500, at most about 1000, at most about 2000, at most about 3000, or at most about 5000 repeats.
  • a cell, population of cells, or subject that does not have a repeat expansion contains at most 5, at most 10, at most 15, at most 20, at most 25, at most 30, at most 35, at most 36, at most 37, at most 38, at most 39, at most 40, at most 45, at most 50, at most 60, at most 70, at most 80, at most 90, or at most 100 copies of the repeat (e.g., CTG, CUG) in the repeat region of the gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene).
  • the repeat e.g., CTG, CUG
  • the gene e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene
  • the disclosure provides a method of treating a nucleotide repeat expansion disorder in a subject, comprising administering a compound disclosed herein to the subject.
  • the repeat expansion disorder comprises expression of repeat- containing mRNA by the subject.
  • the subject is a mammal.
  • the subject is human.
  • the subject is a mouse.
  • administration of a compound provided herein does not exhibit or substantially does not exhibit immunogenicity. In some embodiments, administration of a compound provided herein does not promote or substantially does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, a compound does not activate or substantially does not activate the TLR9 receptor and is not presented or is minimally presented by MHCI or MHCII complexes to the immune system.
  • Compounds provided herein can be locally or systemically administered to a subject in need thereof as a therapeutically-effective amount of a compound that binds to a repeat codon.
  • the subject can comprise a bloodstream, a brain, and a blood-brain-barrier.
  • the compound that binds to the repeat codon can enter the brain by passing from the bloodstream through the blood- brain-barrier into the brain.
  • a compound provided herein or a composition comprising a compound provided herein can be administered to a subject in various forms and by various suitable routes of administration.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in a systemic manner.
  • a compound provided herein or a composition comprising a compound provided herein is administered parenterally.
  • Parenteral administration can be, for example, by bolus injection or by gradual infusion or perfusion over time. Administration can also be by surgical deposition of a bolus or positioning of a medical device.
  • a compound provided herein or a composition comprising a compound provided herein is administered orally.
  • a compound provided herein or a composition comprising a compound provided herein is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intravenous administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by subcutaneous administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intramuscular administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intracerebroventricular administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by oral administration.
  • a compound provided herein or a composition comprising a compound provided herein is administered by intrathecal administration.
  • any aforementioned route of administration can be combined with another route of administration.
  • a compound provided herein can be delivered by a first route of administration, and one or more subsequent maintenance doses of the compound can be delivered by the same or a different route of administration.
  • a compound provided herein or a composition comprising a compound provided herein e.g., a pharmaceutical composition
  • is administered by intramuscular administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.
  • Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrastemal injection, ophthalmic administration, endothelial administration, local administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, transdermal administration (e.g., via emulsion/liposome-mediated methods of delivery with the compound optionally packaged into liposomes), epidural administration, absorption through epithelial or mucocutaneous linings (e g., oral mucosa, rectal and intestinal muco
  • a compound provided herein or a composition comprising a compound provided herein can be administered via a non-invasive method.
  • non-invasive modes of administering can include using a needleless injection device, and topical administration, e.g., eye drops. Multiple administration routes can be employed for efficient delivery.
  • the compositions can be in the form of solid, semi solid or liquid dosage forms, such as, e.g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, e.g., in unit dosage form suitable for single administration of a precise dosage.
  • the composition can be formulated into any suitable dosage form for administration, e.g., aqueous dispersions, liquids, gels, syrups, elixirs, slurries, and suspensions, for administration to a subject or a patient.
  • Solid compositions include, e.g., powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, e.g., solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, e.g., gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions.
  • compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • the composition is formulated into solutions (e.g., for IV administration).
  • the pharmaceutical composition is formulated as an infusion.
  • the pharmaceutical composition is formulated as an injection.
  • a compound provided herein or a composition comprising a compound provided herein can be administered in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • a composition comprising a compound provided herein can be, e.g., an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • hydrogels e.g., of synthetic or natural origin
  • other gelling agents e.g., gel-forming dietary fibers
  • matrix -based formulations e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, e.g., for about 4, about 8, about 12, about 16, or about 24 hours.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, e.g., the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.
  • a pharmaceutical composition disclosed herein can be targeted to any suitable tissue or cell type. Modes, routes, and compositions provided herein can be suitable to target a compound provided herein to a particular tissue, or a subset of tissues.
  • tissues that can be targeted include kidney (e.g., kidney cortex), joints, cartilage, liver, salivary glands, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicles, large intestine mucosa, aortic wall, small intestine mucosa, adrenal gland, stomach mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate putamen, cerebral cortex, substantia nigra, lateral ventricle, choroid plexus, and combinations thereof.
  • Compounds can be introduced into cells by, e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles, and viral and non-viral vectors.
  • Compounds provided herein can also be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine-mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-0 permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non-endocytic methods of delivery.
  • permeabilization e.g., streptolysin-0 permeabilization, anionic peptide permeabilization
  • electroporation e.g., electroporation, and various non-invasive non-endocytic methods of delivery.
  • the method of delivery can depend at least on the cells to be treated and the location of the cells. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor mediated uptake, or viral vectors.
  • a compound disclosed herein is delivered via an implantable device, e.g., synthetic implant design.
  • Compounds provided herein can be administered in any physiologically and/or pharmaceutically acceptable vehicle or carrier.
  • pharmaceutically acceptable carriers include saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil/water emulsions or triglyceride emulsions, tablets, and capsules.
  • PBS phosphate buffered saline
  • emulsions such as oil/water emulsions or triglyceride emulsions, tablets, and capsules.
  • suitable physiologically acceptable carrier can vary depending upon the chosen mode of administration.
  • a pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • prodrugs of a compound provided herein can be covalently bonded carriers that release a compound in vivo when administered to a subject.
  • Prodrugs can be prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, to yield the biologically active compound.
  • Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups of compounds provided herein.
  • esters can be used, such as methyl esters and ethyl esters.
  • liposomes can be used to facilitate uptake of a compound provided herein into cells.
  • Hydrogels can also be used as vehicles for compound administration.
  • a compound provided herein can be administered in microspheres or microparticles.
  • the use of gas-filled microbubbles complexed with a compound provided herein can enhance delivery to target tissues.
  • Sustained release compositions can also be used, including, e.g., semipermeable polymeric matrices in the form of shaped articles such as films or microcapsules.
  • a compound provided herein is administered to a mammalian subject, e.g., human or domestic animal that is exhibiting the symptoms of a polynucleotide repeat expansion disorder.
  • Compounds provided herein can selectively reduce expression of a mutant protein in the subject.
  • the subject is a human subject, e.g., a patient diagnosed as having a polynucleotide repeat disease.
  • a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered orally.
  • a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered intravenously.
  • the subject is a vertebrate.
  • the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
  • the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a patient is a non-human patient. In some embodiments, a patient is a veterinary patient.
  • a patient and a subject are the same species. In some embodiments, a subject and a patient are human.
  • a patient and a subject are different species.
  • a subject is human and a patient is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • a patient is human and a subject is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • a non-human vertebrate for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • An effective in vivo treatment regimen using the compounds provided herein can vary according to the duration, dose, frequency, and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy can require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome.
  • the efficacy of an in vivo administered compound provided herein can be determined from biological samples (e.g., tissue, blood, urine) taken from a subject prior to, during, and subsequent to administration of the compound.
  • Assays of such samples can include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, e.g., by an electrophoretic gel mobility assay; and (2) monitoring the amount of a mutant mRNA or protein in relation to a reference wild-type mRNA or protein as determined by standard techniques such as RT-PCR, Northern blotting, EL1SA, or Western blotting.
  • the compound provided herein is actively taken up by mammalian cells.
  • the compound provided herein can be conjugated to a transport moiety (e.g., transport peptide) as described herein to facilitate such uptake.
  • Compounds provided herein can be administered to subjects to treat (prophylactically or therapeutically) disorders associated with aberrant expression of a mRNA or protein produced from a mutant polynucleotide repeat containing allele.
  • pharmacogenomics i.e., the study of the relationship between an individual’s genotype and the individual’s response to a foreign compound or drug
  • Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug.
  • a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and/or therapeutic regimen of treatment with the therapeutic agent.
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the dosage e.g., therapeutically-effective amount
  • for a compound described herein can be in any amount necessary.
  • a compound described herein can be present in a composition or a unit dose in a range of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg,
  • a compound described herein can be present in a composition or a unit dose in a range of from about 1 ⁇ g to about 2000 ⁇ g; from about 5 ⁇ g to about 1000 ⁇ g, from about 10 ⁇ g to about 25 ⁇ g, from about 50 ⁇ g to about 250 ⁇ g, from about 100 ⁇ g to about 200 ⁇ g, from about 1 mg to about 50 ⁇ g.
  • a compound described herein can be present in a composition or a unit dose in an amount of about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about
  • a composition is present in a composition or a unit dose in an amount that is at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5
  • a composition is present in a composition or a unit dose in an amount that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, at most about 0.2 mg, at most about 0.3 mg, at most about 0.4 mg, at most about 0.5 mg, at most about 0.6 mg, at most about 0.7 mg, at most about 0.8 mg, at most about 0.9 mg, at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5
  • a dose (e.g., a unit dose) is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10
  • a dose is at least about 0.001 mg/kg, at least about 0.002 mg/kg, at least about 0.003 mg/kg, at least about 0.004 mg/kg, at least about 0.005 mg/kg, at least about 0.006 mg/kg, at least about 0.007 mg/kg, at least about 0.008 mg/kg, at least about 0.009 mg/kg, at least about 0.01 mg/kg, at least about 0.02 mg/kg, at least about 0.03 mg/kg, at least about 0.04 mg/kg, at least about 0.05 mg/kg, at least about 0.06 mg/kg, at least about 0.07 mg/kg, at least about 0.08 mg/kg, at least about 0.09 mg/kg, at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg/kg, at least about 0.6 mg/kg, at least about 0.7 mg
  • a dose is at most about 0.001 mg/kg, at most about 0.002 mg/kg, at most about 0.003 mg/kg, at most about 0.004 mg/kg, at most about 0.005 mg/kg, at most about 0.006 mg/kg, at most about 0.007 mg/kg, at most about 0.008 mg/kg, at most about 0.009 mg/kg, at most about 0.01 mg/kg, at most about 0.02 mg/kg, at most about 0.03 mg/kg, at most about 0.04 mg/kg, at most about 0.05 mg/kg, at most about 0.06 mg/kg, at most about 0.07 mg/kg, at most about 0.08 mg/kg, at most about 0.09 mg/kg, at most about 0.1 mg/kg, at most about 0.2 mg/kg, at most about 0.3 mg/kg, at most about 0.4 mg/kg, at most about 0.5 mg/kg, at most about 0.6 mg/kg, at most about 0.7
  • a dose is from about 0.1 mg/kg to about 2000 mg/kg, from about 1 mg/kg to about 2000 mg/kg, from about 5 mg/kg to about 1000 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 50 mg/kg to about 250 mg/kg, from about 100 mg/kg to about 200 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg, from about 250 mg/kg to about 300 mg/kg, from about 300 mg/kg to about 350 mg/kg, from about 350 mg/kg to about 400 mg/kg, from about 400 mg/kg to about 450 mg/kg, from about 450 mg/kg to about 500 mg/kg, from about 500 mg/kg to about 550 mg/kg, from about 550 mg/kg, from about 550 mg/kg
  • compositions and formulations described herein can comprise, for example, a compound provided herein at any suitable concentration.
  • a formulation can comprise a composition provided herein at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg//
  • a formulation provided herein comprises a compound provided herein at a concentration of at least about 0.001 mg/mL, at least about 0.002 mg/mL, at least about 0.003 mg/mL, at least about 0.004 mg/mL, at least about 0.005 mg/mL, at least about 0.006 mg/mL, at least about 0.007 mg/mL, at least about 0.008 mg/mL, at least about 0.009 mg/mL, at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.2 mg/mL, at least about 0.3 mg/mL, at least about 0.4 mg/m
  • a formulation provided herein comprises a compound provided herein at a concentration of at most about 0.002 mg/mL, at most about 0.003 mg/mL, at most about 0.004 mg/mL, at most about 0.005 mg/mL, at most about 0.006 mg/mL, at most about 0.007 mg/mL, at most about 0.008 mg/mL, at most about 0.009 mg/mL, at most about 0.01 mg/mL, at most about 0.02 mg/mL, at most about 0.03 mg/mL, at most about 0.04 mg/mL, at most about 0.05 mg/mL, at most about 0.06 mg/mL, at most about 0.07 mg/mL, at most about 0.08 mg/mL, at most about 0.09 mg/mL, at most about 0.1 mg/mL, at most about 0.2 mg/mL, at most about 0.3 mg/mL, at most about 0.4 mg/mL, at most about 0.5 mg/mL,
  • a formulation provided herein comprises a compound provided herein at a concentration of about 1 mg/mL to about 2000 mg/mL; from about 5 mg/mL to about 1000 mg/mL, from about 10 mg/mL to about 25 mg/mL, from about 50 mg/mL to about 250 mg/mL, from about 100 mg/mL to about 200 mg/mL, from about 1 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 250 mg/mL, from about 250 mg/mL to about 300 mg/mL, from about 300 mg/mL to about 350 mg/mL, from about 350 mg/mL to about 400 mg/mL, from about 400 mg/mL to about 450 mg/mL, from about 450 mg/mL to about 500 mg/mL, from
  • a formulation of the disclosure delivers about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 0.1 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 0.2 mg/kg AED of a compound of the disclosure.
  • a formulation of the disclosure delivers about 0.3 mg/kg AED of a compound of the disclosure.
  • An approximate dose can be predicted or determined on the basis of data existing in other species.
  • allometric scaling can be used to exchange a drug dose based on normalization of dose to body surface area. Allometric scaling considers the sizes of individual species based on body surface area, which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size.
  • a no observed adverse effect level (NOAEL) is first determined in an animal species, the NOAEL is converted to a human equivalent dose (HED), an appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.
  • NOAEL no observed adverse effect level
  • NOAEL the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from animal experiments to determine a safe starting dose. NOAEL values can be converted to HED on the basis of the body surface correction factor using appropriate scaling factors from animal species. TABLE 5 lists HED calculation guidelines based on body surface areas. HED is determined using the equation:
  • HED Animal NOAEL (mg/kg) x (Weight animai [kg]/Weight human [kg]) (1'067) [00240]
  • the HED is divided by a factor value of 10 to increase safety of the first human dose.
  • the safety factor is accountable for differences in physiological and biological processes between human and animal species.
  • the correction factor (K m ) is estimated by dividing the average body weight (kg) of a species to its body surface area (m 2 ).
  • the K m factor values of various animal species of TABLE 5 is used to estimate the HED as:
  • conversion between species based on mg/m 2 is not supported for drugs administered by topical, nasal, subcutaneous, or intramuscular routes, as well as proteins administered parenterally with molecular weight >100,000 Daltons.
  • TABLE 6 provides animal equivalent dose (AED) calculation guidelines based on body surface area.
  • the animal equivalent dose (AED) can also be calculated on the basis of body surface area by either dividing or multiplying the human dose (mg/kg) by the K m ratio provided in TABLE 6.
  • AED can be calculated using the equation:
  • AED (mg/kg) Human doses (mg/kg) x K m ratio
  • HED conversion (mg/kg) is also based on body surface area normalization. The conversion can be made by dividing the NOAEL in appropriate species by the conversion factor. TABLE 7 provides guidelines for maximum injection volume, by species, site location, and gauge size. Injection volume of parenteral formulation is calculated by the following equation:
  • Injection volume (mL) [Animal weight (kg) x Animal doses (mg/kg)] / Concentration (mg/kg)
  • Compounds disclosed herein can be effective for reducing an expression level of a disease-causing Huntingtin gene in a subject.
  • Various analytical techniques can be used to determine or quantify gene expression level, mRNA expression level, or protein expression level in the subject, e g., in a tissues and/or other samples collected from study patients (e.g., blood, plasma, urine, feces, etc).
  • Non-limiting examples of techniques to determine gene expression level include sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), immunoassaying, immunoblotting, western blotting, fluorescent western blotting, enzyme-linked immunosorbent assay (EL1SA), and AlphaL1SA® assaying.
  • a) in a first control group six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 10% lesser than is a mean expression of the non-
  • the nucleic acid molecule associated with Huntington’s disease is a mRNA sequence transcribed from the disease-causing Huntingtin gene.
  • the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 10% lesser than to about 20% lesser than a mean expression of the non-disease-causing Huntingtin gene in the first control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 20% lesser than to about 40% lesser than a mean expression of the disease-causing Huntingtin gene in the second control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 20% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
  • the present disclosure provides a method of treating Huntington’s disease, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
  • a) in a first control group six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 10% lesser than is a mean expression of the non-
  • the nucleic acid molecule associated with Huntington’s disease is a mRNA sequence transcribed from the disease-causing Huntingtin gene.
  • the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 10% lesser than to about 20% lesser than a mean expression of the non-disease-causing Huntingtin gene in the first control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 20% lesser than to about 40% lesser than a mean expression of the disease-causing Huntingtin gene in the second control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 20% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
  • the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
  • a) in a first control group six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 5% greater than is a mean expression of the non
  • the nucleic acid molecule associated with Huntington’s disease is a DNA sequence of the disease-causing Huntingtin gene.
  • the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 5% greater than to about 15% greater than the mean expression of the non-disease- causing Huntingtin gene in the first control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 25% lesser than the mean expression of the disease-causing Huntingtin gene in the second control group.
  • the mean expression of the disease- causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 30% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
  • the present disclosure provides a method of treating Huntington’s disease, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
  • a) in a first control group six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 5% greater than is a mean expression of the nond
  • the nucleic acid molecule associated with Huntington’s disease is a DNA sequence of the disease-causing Huntingtin gene.
  • the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 5% greater than to about 15% greater than the mean expression of the non-disease- causing Huntingtin gene in the first control group.
  • the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 25% lesser than the mean expression of the disease-causing Huntingtin gene in the second control group.
  • the mean expression of the disease- causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 30% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
  • the compounds of the disclosure show non-lethal toxicity.
  • a pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
  • Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
  • a subject is a patient.
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
  • a pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject.
  • Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).
  • Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremophor, DMSO, and potassium phosphate buffer.
  • compositions can be formulated for intravenous administration.
  • the phannaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject.
  • the compounds of the disclosure can be applied to an accessible body cavity.
  • the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
  • therapeutically-effective amounts of the compounds described herein can be administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
  • compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically- acceptable salt form.
  • Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions and creams.
  • compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
  • a composition of the disclosure can be, for example, an immediate release form or a controlled release formulation.
  • An immediate release formulation can be formulated to allow the compounds to act rapidly.
  • Non-limiting examples of immediate release formulations include readily dissolvable formulations.
  • a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
  • Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • hydrogels e.g., of synthetic or natural origin
  • other gelling agents e.g., gel-forming dietary fibers
  • matrix-based formulations e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through
  • a controlled release formulation is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
  • a controlled release formulation can be a sustained release form.
  • a sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
  • Multiple therapeutic agents can be administered in any order or simultaneously.
  • a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent.
  • the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills.
  • the agents can be packed together or separately, in a single package or in a plurality of packages.
  • One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.
  • Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary.
  • the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition.
  • the compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
  • a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged injectables, vials, or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.
  • compositions provided herein can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins.
  • the other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
  • the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
  • nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
  • Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
  • anti-infectives i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
  • Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds.
  • Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine).
  • a liposome design can employ surface ligands for attaching to unhealthy tissue.
  • Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV).
  • LUV multilamellar vesicle
  • SUV small unilamellar vesicle
  • LUV large unilamellar vesicle
  • Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues.
  • Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells.
  • targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti -adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
  • compositions of the disclosure can be packaged as a kit.
  • a kit includes written instructions on the administration/use of the composition.
  • the written material can be, for example, a label.
  • the written material can suggest conditions methods of administration.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • the written material can be a label.
  • the label can be approved by a regulatory agency, for example the U S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
  • FDA U S. Food and Drug Administration
  • EMA European Medicines Agency
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guani dinoalkyl; ii) C(0)-alkyl; and iii) guani di noalkyl.
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG) Z (SEQ ID NO: 135) or (CTG) Z (SEQ ID NO: 182), wherein z is an integer from 1-100, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guanidinoalkyl.
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG) Z (SEQ ID NO: 135) or (CTG) Z (SEQ ID NO: 182), wherein z is an integer from 1-100 (SEQ ID NO: 135), wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG) Z (SEQ ID NO: 135) or (CTG) Z (SEQ ID NO: 182), wherein z is an integer from 1-100 (SEQ ID NO: 135), wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
  • a compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
  • each of the side chains is independently aminoalkyl, guanidinoalkyl, ureidolalkyl, amidinoalkyl, morpholinoalkyl, piperidinylalkyl, piperazinylalkyl, or pyrrolidinylalkyl.
  • each guanidinoalkyl is independently H, 3 -guani dinoprop- 1-yl, or 4- guani dinobut- 1 -y 1.
  • nucleic acid sequence contains a subsequence that is (CAG) Z (SEQ ID NO: 135) or (CTG) z (SEQ ID NO: 182), wherein z is an integer from 1-100.
  • a compound comprising a structure that is:
  • A-Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent;
  • C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • Z is a peptide nucleic acid sequence
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent
  • L6 is a linker group or absent; and or a pharmaceutically-acceptable salt or ionized form thereof.
  • Z is a peptide nucleic acid sequence according to PNA SEQ NO: 1, PNA SEQ NO: 2, PNA SEQ NO: 3, PNA SEQ NO: 4, PNA SEQ NO: 5, PNA SEQ NO: 6, PNA SEQ NO: 7, PNA SEQ NO: 8, PNA SEQ NO: 9, PNA SEQ NO: 10, PNA SEQ NO: 11, PNA SEQ NO: 12, PNA SEQ NO: 13, PNA SEQ NO: 14, PNA SEQ NO: 15, PNA SEQ NO: 16, PNA SEQ NO: 17, PNA SEQ NO: 18, PNA SEQ NO: 19, PNA SEQ NO: 20, PNA SEQ NO: 21, PNA SEQ NO: 22, PNA SEQ NO: 23, PNA SEQ NO: 34,
  • PNA SEQ NO: 30 PNA SEQ NO: 31, PNA SEQ NO: 32, PNA SEQ NO: 33, PNA SEQ NO: 34, PNA SEQ NO: 35, PNA SEQ NO: 36, PNA SEQ NO: 37, or PNA SEQ NO: 38.
  • Z is a peptide nucleic acid sequence complementary to a nucleic acid sequence selected from the group consisting of: CAG, CAGC, CAGCA, CAGCAG, CAGCAGC, CAGCAGCA, CAGCAGCAG, CAGCAGCAGC (SEQ ID NO: 96), CAGCAGCAGCA (SEQ ID NO: 97),
  • CAGCAGCAGCAG (SEQ ID NO: 98), CAGCAGCAGCAGC (SEQ ID NO: 99), CAGCAGCAGC AGCA (SEQ ID NO: 100), CAGCAGCAGCAGC AG (SEQ ID NO: 101), CAGCAGCAGC AGCAGC (SEQ ID NO: 102), CAGCAGCAGCAGC AGCA (SEQ ID NO: 103), CAGC AGCAGC AGCAGC AG (SEQ ID NO: 104), CAGCAGCAGCAGCAGCAGC (SEQ ID NO: 105), CAGC AGCAGC AGCAGC AGCA (SEQ ID NO: 106),
  • CAGCAGC AGCAGC AGCAGC AG (SEQ ID NO: 107), CAGC AGCAGC AGCAGC AGCAGC (SEQ ID NO: 108), CAGCAGCAGCAGCAGCAGC AGCA (SEQ ID NO: 109),
  • CAGC AGCAGC AGCAGCAGCAGC AG (SEQ ID NO: 110), AGC, AGCA, AGCAG, AGCAGC, AGCAGC A, AGC AGCAG, AGC AGC AGC, AGC AGC AGC A (SEQ ID NO: 151), AGCAGC AGCAG (SEQ ID NO: 152), AGCAGCAGCAGC (SEQ ID NO: 153),
  • AGC AGC AGC AGCA (SEQ ID NO: 154), AGC AGC AGC AGC AG (SEQ ID NO: 155), AGCAGC AGCAGCAGC (SEQ ID NO: 156), AGC AGCAGCAGCAGC A (SEQ ID NO: 157), AGC AGC AGC AGC AGC AG (SEQ ID NO: 158), AGC AGC AGC AGCAGC AGC (SEQ ID NO: 159), AGCAGCAGC AGCAGCAGC A (SEQ ID NO: 160), AGC AGCAGCAGC AGC AGC AG (SEQ ID NO: 161), AGCAGCAGCAGCAGCAGCAGC (SEQ ID NO: 162),
  • each R 1 is independently alkyl that is substituted and R alpha1 is H, or each R 1 is H and each R alpha1 is independently alkyl that is substituted.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2- thiomethyleth-l-yl, 4-aminobut-l-yl, 3-aminoprop-l-yl, l-H-imidazol-4-ylmethyl, 1 -H-indol-3- ylmethyl, benzyl, 4-hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3- guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each alkyl that is substituted is independently a guanidinoalkyl group or a hydroxyalkyl group.
  • each alkyl that is substituted is independently 3 -guani dinoprop- 1-yl, or 4-guanidinobut-l-yl.
  • Z is a peptide nucleic acid sequence according to PNA SEQ NO: 2, PNA SEQ NO: 3, PNA SEQ NO: 4, PNA SEQ NO: 5, PNA SEQ NO: 6, PNA SEQ NO: 7, PNA SEQ NO: 8, PNA SEQ NO: 9, PNA SEQ NO: 10, PNA SEQ NO: 11, PNA SEQ NO: 15, PNA SEQ NO: 19, PNA SEQ NO: 23, PNA SEQ NO: 34, PNA SEQ NO: 25, PNA SEQ NO: 26, PNA SEQ NO: 27, PNA SEQ NO: 28, PNA SEQ NO: 29, PNA SEQ NO: 30, PNA SEQ NO: 31, PNA SEQ NO: 32, PNA SEQ NO: 33, or PNA SEQ NO: 36.
  • a compound comprising a structure that is: wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R 3 is independently alkyl that is unsubstituted or substituted or H; each R 4 is independently R 2 ; each R 5 is independently alkyl that is unsubstituted or substituted or H; each R 6 is independently R 2 ; each R 7 is independently alkyl that is unsubstituted or substituted or H; each R 8 is independently R
  • C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • each R alpha1 is H.
  • each R alpha1 is independently alkyl that is unsubstituted.
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazol-4-ylmethyl, 1 -7/-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R alpha1 is independently a guanidinoalkyl group or a hydroxy
  • each R alpha1 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
  • each R alphal is H.
  • each R alpha4 is independently alkyl that is unsubstituted.
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 H -imidazoM-ylmethyl, 1 - H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R alpha4 is independently a guanidinoalkyl group or a hydroxyalkyl group.
  • each R alpha4 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, N-methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R 1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a L'-methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R 7 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
  • each R 3 is independently an alkyl group that is unsubstituted or substituted, and each R 5 is independently a group that is not substituted alkyl.
  • each R 3 is independently a guanidinoalkyl group
  • each R 5 is independently a group that is not guanidinoalkyl.
  • each R alpha2 is independently an alkyl group that is unsubstituted or substituted, and R alpha3 is independently a group that is not substituted alkyl.
  • each R alpha2 is independently a guanidinoalkyl group
  • each R alpha3 is independently a group that is not guanidinoalkyl.
  • each R alpha2 is independently a hydroxy alkyl group
  • each R alpha3 is independently a group that is not hydroxy alkyl.
  • a compound comprising a structure that is: wherein: the number of units with variables defined independently is at least 3;
  • .Y-Terminus is H, acyl, a group that together with the nitrogen atom to which N--Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R 1 is independently alkyl that is unsubstituted or substituted or H; each R alpha is independently alkyl that is unsubstituted or substituted or H; each R 2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R 2 groups in the structure are independently methyl substituted with a heterocycle;
  • C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
  • PEP1 is a peptide sequence or absent
  • PEP2 is a peptide sequence or absent
  • SOL1 is a water-solubilizing group or absent
  • SOL2 is a water-solubilizing group or absent
  • PNA1 is a peptide nucleic acid sequence or absent
  • PNA2 is a peptide nucleic acid sequence or absent;
  • L1 is a linker group or absent;
  • L2 is a linker group or absent
  • L3 is a linker group or absent
  • L4 is a linker group or absent
  • L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmcthyl, 1 -H-indol-3-ylmcthyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • each R alpha is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
  • R 1 is H or -CH 2 OH; and R 2 i iss a fifth unit is present, and in the fifth unit: a sixth unit is present, and in the sixth unit: a seventh unit is present, and in the seventh unit:
  • R 1 is H or -CH 2 OH; and R 2 i iss an eighth unit is present, and in the eighth unit: a ninth unit is present, and in the ninth unit: a tenth unit is present, and in the tenth unit: an eleventh unit is present, and in the eleventh unit: a twelfth unit is present, and in the twelfth unit: a thirteenth unit is present, and in the thirteenth unit: a fourteenth unit is present, and in the fourteenth unit: a fifteenth unit is present or absent, and in the fifteenth unit: a sixteenth unit is present or absent, and in the sixteenth unit: a seventeenth unit is present or absent, and in the seventeenth unit: an eighteenth unit is present or absent, and in the eighteenth unit: nineteenth unit is present or absent, and in the nineteenth unit: a twentieth unit is present or absent, and in the twentieth unit: an twenty-first unit is present or absent, and in the twenty-first unit: a twenty-second unit is present or absent,
  • each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
  • each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
  • each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH 2 , a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
  • each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazol-4-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
  • PEP1 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
  • PEP2 is a sequence that is -(/9-Arg)-(/9-Arg)-(/9-Arg)-(/9-Arg)- (SEQ ID NO: 181).
  • PEP2 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148).
  • PEP2 is a sequence that is -Cys'-Lcu-Glu-Val-Scr-Arg-Lys-Asn-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144).
  • PEP2 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145).
  • PEP2 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys 2 -, wherein Cys 1 and Cys 2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146).
  • R la is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • R la is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
  • R la is H, alkyl, or a nitrogen atom protecting group
  • R 2a is O, NH, N(alkyl), or N(Pg N ), wherein Pg N is a nitrogen atom protecting group;
  • R 3a is H, alkyl, or a nitrogen atom protecting group
  • R 4a is H, alkyl, or a nitrogen atom protecting group
  • R 5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
  • Q is O, NH, N(alkyl), or N(Pg N ); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.

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Abstract

The present disclosure relates to compounds useful for the detection or modulation of target nucleic acids containing trinucleotide repeats. The present disclosure further relates to methods for treatment of trinucleotide repeat disorders such as polyglutamine diseases, which can include administration of oligonucleotide analogues that can bind pathogenic nucleotide repeats in DNA or RNA.

Description

PEPTIDE NUCLEIC ACID THERAPEUTICS FOR TRINUCLEOTIDE REPEAT
DISORDERS
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 63/197,797, filed June 7, 2021, and U.S. Provisional Application No. 63/250,058, filed September 29, 2021, each of which is entirely incorporated herein by reference.
BACKGROUND
[0002] Hereditary disorders are characterized by genetic abnormalities that can range from a single base mutation in a single gene to the addition or deletion of an entire chromosome or set of chromosomes. One such hereditary disorder is Huntington’s disease, a neurodegenerative disorder caused by a single defective gene on chromosome 4.
SUMMARY
[0003] In some embodiments, the present disclosure provides a compound comprising:
1) a pharmacophore that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000003_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[0004] In some embodiments, the present disclosure provides a compound comprising a structure that is: N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-£-
Figure imgf000004_0001
wherein: the number of units with variables defined independently is at least 11;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a gene associated with a neurodegenerative disease phenotype.
[0005] In some embodiments, the present disclosure provides a compound comprising an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000005_0001
wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[0006] Additional aspects and/or advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and/or described. As will be realized, the present disclosure is capable of other and/or different embodiments, and/or its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and/or description are to be regarded as illustrative in nature, and/or not as restrictive.
INCORPORATION BY REFERENCE
[0007] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually.
BRIEF DESCRIPTION OF THE DRAWINGS [0008] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and/or advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and/or the accompanying drawings (also “figure” and “FIG.” herein), of which: [0009] FIG. 1, Panel A illustrates relative HTT protein expression in mice treated with Compound 76 or vehicle. FIG. 1, Panel B illustrates a schematic of transcription engagement by PNA binding to mutant HTT mRNA.
[0010] FIG. 2, Panel A illustrates relative HTT protein expression in mice treated with Compound 77 or vehicle. FIG. 2, Panel B illustrates a schematic of genome engagement by PNA binding to mutant HTT DNA.
[0011] FIG. 3 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases) or hydrogen.
[0012] FIG. 4 illustrates the structure of Compound 1.
[0013] FIG. 5 illustrates the structure of Compound 2.
[0014] FIG. 6 illustrates the structure of Compound 16.
[0015] FIG. 7 illustrates the structure of Compound 52.
[0016] FIG. 8 illustrates the structure of Compound 57.
[0017] FIG. 9 illustrates the structure of Compound 58.
[0018] FIG. 10 illustrates the structure of Compound 59.
[0019] FIG. 11 illustrates the structure of Compound 75.
[0020] FIG. 12 illustrates the structure of Compound 76.
[0021] FIG. 13 illustrates the structure of Compound 77.
DETAILED DESCRIPTION
[0022] While various embodiments of the invention have been shown and/or described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and/or substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
[0023] Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with cognitive impairment, dementia, and loss of motor coordination. While the disease primarily manifests in the brain, HD can be considered a whole-body disease. Conditions associated with HD include weight loss, muscle atrophy, glucose intolerance, osteoporosis, testicular atrophy, heart failure, and/or cardiac abnormalities.
[0024] HD associated with a defective gene, the Huntingtin (HTT) gene, on chromosome 4. Expansion of CAG trinucleotide repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the HTT gene results in an abnormal mutant protein (mHTT), which can cause gradual neuronal cell damage. The progressive and heritable increase in length of CAG repeats encode a polyglutamine tract in the coding region of the HTT gene. These CAG repeats can increase in number from one generation to another. The normal allele of the HTT gene can comprise fewer than 36 CAG repeats, whereas the mutant allele can comprise more than 36 repeats. Many HD patients carry one normal allele and a mutant disease-causing allele. Normal or wild type HTT is widely expressed and important for cell signaling, transcriptional regulation, molecular trafficking, and axonal transport, modulating brain-derived neurotrophic factor (BDNF) production. Aberrant accumulation of CAG repeats can confer a toxic gain-of-function phenotype, causing the protein to aggregate and form protein deposits (inclusion bodies). Neuronal loss can start in the striatum and progress to the cortex. Disease severity generally reflects the extent of expanded repeats in the mutant HTT protein.
[0025] Provided herein are compounds, compositions, and methods for the treatment of HD. These compounds can, for example, reduce or inhibit expression of the disease-causing HTT gene by targeting nucleic acids associated with the mutant HTT expression, e.g., RNA or DNA precursors of mutant HTT. For example, the compounds can bind to nucleic acid molecule associated with HD, thereby reducing mRNA expression or protein expression of the disease- causing HTT gene.
Compounds of the disclosure.
[0026] Provided herein are compounds and compositions thereof that reduce expression of the disease-causing HTT gene and compositions thereof. Non-limiting examples of compounds of the disclosure are provided in TABLE 1. Residue structures, pendant nucleobase identities (when present), and monomer chemical names associated with the symbols used in the structure codes of TABLE 1 and TABLE 2 are provided in TABLE 3. Compounds can be provided as a pharmaceutically-acceptable salt, tautomer, or ionized form thereof.
TABLE 1
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
aUnless otherwise noted, all C-termini are amidated. bThe structure code corresponding to each PNA SEQ NO is provided in TABLE 2. For example, the structure code of Compound 4 is K*GpBxTpBxBx[Z]BxBxGpK*, which is K*GpBxTpBxBxTpGnCnTpGnCpTnGpCnTnGpBxBxGpK*. cSubsequences(s) of structure code within braces (e.g., “{TGNYKALHPHNG}”), when present, correspond to SEQ ID NOs provided in this column, listed from first to last occurrence in N to C terminal direction. When more than one subsequence is encompassed within braces in a single compound, corresponding SEQ ID NOs are listed from first to last occurrence in N to C terminal direction. TABLE 2
Figure imgf000010_0001
TABLE 3
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
aProteinogenic amino acid residues in compounds provided in TABLE 1 are represented by the following one-letter codes: A: L-alanine, R: L.-arginine, N: L- sparagine, D L--aspartic acid, C: L-cysteine, E: L-glutamic acid, Q: L-glutamine, G: glycine, H: L-histidine, I: L-isoleucine, L: L- leucine , K: L-lysine, M: L-methionine, F: L-phenylalanine, P: L-proline, S: L-serine, T: L- threonine, W: L-tryptophan, Y: L-tyrosine, V: L-valine. bAn antipode of a chiral residue presented in TABLE 3 is represented in TABLE 1 by the code of the chiral residue followed by an asterisk (*). For example, R* represents /7-arginine. cIn TABLE 1, C(&) represents an L-cysteine residue that is covalently bound via the sulfur atom of its side chain to a sulfur atom of another L-cysteine residue represented by C(&). For example, a compound having the sequence code GC(&)GGGGGC(&)G (SEQ ED NO: 134) comprises two cysteine residues that are bound to each other via an intrachain disulfide bond. dFor each residue, a chemical name is provided for the corresponding unincorporated monomer.
[0027] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guani dinoalkyl.
[0028] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
[0029] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
[0030] In some embodiments, the structure is a peptide nucleic acid structure. In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease phenotype. [0031] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG)n (SEQ ID NO: 135) or (CTG)n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guanidinoalkyl.
[0032] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG)n (SEQ ID NO: 135) or (CTG)n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guani dinoalkyl.
[0033] In some embodiments, the disclosure provides a compound comprising a structure, wherein the structure binds to a sequence of nucleic acids that contains a subsequence that is (CAG)n (SEQ ID NO: 135) or (CTG)n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH. wherein the structure binds to the sequence of nucleic acids at the subsequence that is (CAG)n (SEQ ID NO: 135) or (CTG)n (SEQ ID NO: 182).
[0034] In some embodiments, the sequence of nucleic acids is a DNA sequence. In some embodiments, the sequence of nucleic acids is a DNA sequence, and the subsequence is (CTG)n (SEQ ID NO: 182). In some embodiments, the sequence of nucleic acids is a RNA (e.g., mRNA) sequence. In some embodiments, the sequence of nucleic acids is a RNA (e.g., mRNA) sequence, and the subsequence is (CAG)n(SEQ ID NO: 135).
[0035] In some embodiments, the disclosure provides a composition comprising a compound that is therapeutically-effective for treatment of a neurodegenerative disease, wherein the compound comprises a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-J-
Figure imgf000020_0001
wherein: the number of units with variables defined independently is at least 11; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, OMe, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and
L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0036] In some embodiments, PEP1 is absent. In some embodiments, PEP1 is the peptide sequence. In some embodiments, the peptide sequence of PEP 1 is a nuclear localization sequence. In some embodiments, PEP1 is a sequence that is -(//-Arg)-(//-Arg)-(/J-Arg)-(/J- Arg)- (SEQ ID NO: 181). In some embodiments, PEP1 is a sequence that is -Tyr-Gly-Arg-Lys- Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149). In some embodiments, PEP1 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148). In some embodiments, PEP1 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141). In some embodiments, PEP1 is -Cys'-Leu-Ser-Ser-Arg-Leu-Asp-Ala-Cys2- , wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142). In some embodiments, PEP1 is a sequence that is -Cys1-Ala-Gly-Ala-Leu-Cys2-Tyr-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143). In some embodiments, PEP1 is a sequence that is -Cys'-Leu-Glu-Val-Ser-Arg-Lys-Asn-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144). In some embodiments, PEP1 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82). In some embodiments, PEP1 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145). In some embodiments, PEP1 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146). In some embodiments, PEP1 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
[0037] In some embodiments, PEP2 is absent. In some embodiments, PEP2 is the peptide sequence. In some embodiments, the peptide sequence of PEP2 is a nuclear localization sequence. In some embodiments, PEP2 is a sequence that is -(I)-Arg)-(1)-Arg)-(1)-Arg)-(1)- Arg)- (SEQ ID NO: 181). In some embodiments, PEP2 is a sequence that is -Tyr-Gly-Arg-Lys- Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149). In some embodiments, PEP2 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148). In some embodiments, PEP2 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141). In some embodiments, PEP2 is -Cys'-Leu-Ser-Ser-Arg-Leu-Asp-Ala-Cys2- , wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142). In some embodiments, PEP2 is a sequence that is -Cys1-Ala-Gly-Ala-Leu-Cys2-Tyr-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143). In some embodiments, PEP2 is a sequence that is -Cys'-Leu-Glu-Val-Ser-Arg-Lys-Asn-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144). In some embodiments, PEP2 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82). In some embodiments, PEP2 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145). In some embodiments, PEP2 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146). In some embodiments, PEP2 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
[0038] In some embodiments, SOL1 is absent. In some embodiments, SOL1 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL1 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL1 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL1 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [0039] In some embodiments, the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000023_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[0040] In some embodiments, the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000023_0002
wherein p is an integer that is 1-1,000.
[0041] In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7.
[0042] In some embodiments, the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000024_0001
Rlb is H, alkyl, or a nitrogen atom protecting group;
R2b is O, NH, N(alkyl), or N(PgN1), wherein PgN1 is a nitrogen atom protecting group; R’b is H, alkyl, or a nitrogen atom protecting group;
R4b is H, alkyl, or a nitrogen atom protecting group;
R5b is alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R5b groups in the structure are independently methyl substituted with a heterocycle;
J is O, NH, N(alkyl), or N(PgN1); z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and v is an integer that is 1-1,000.
[0043] In some embodiments, the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000024_0002
wherein v is an integer that is 1-1000.
[0044] In some embodiments, v is an integer that is 1-100. In some embodiments, v is an integer that is 1-50. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, v is an integer that is 3, 4, 5, 6, or 7. In some embodiments, v is an integer that is 6.
[0045] In some embodiments, SOL2 is absent. In some embodiments, SOL2 is the water- solubilizing group. In some embodiments, the water-solubilizing group of SOL2 is a peptide sequence. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH. In some embodiments, the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH. In some embodiments, the water- solubilizing group of SOL2 is a polyethyleneglycol group. In some embodiments, the water- solubilizing group of SOL2 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg-. [0046] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000025_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[0047] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000025_0002
wherein p is an integer that is 1-1,000.
[0048] In some embodiments, p is an integer that is 1-100. In some embodiments, p is an integer that is 1-50. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is an integer that is 5, 6, 7, 8, or 9. In some embodiments, p is an integer that is 6, 7, or 8. In some embodiments, p is an integer that is 7.
[0049] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000026_0001
Rlb is H, alkyl, or a nitrogen atom protecting group;
R2b is O, NH, N(alkyl), or N(PgN1), wherein PgN1 is a nitrogen atom protecting group; R’b is H, alkyl, or a nitrogen atom protecting group;
R4b is H, alkyl, or a nitrogen atom protecting group;
R5b is alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R5b groups in the structure are independently methyl substituted with a heterocycle;
J is O, NH, N(alkyl), or N(PgN1); z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and v is an integer that is 1-1,000.
[0050] In some embodiments, the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000026_0002
wherein v is an integer that is 1-1000.
[0051] In some embodiments, v is an integer that is 1-100. In some embodiments, v is an integer that is 1-50. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, v is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, v is an integer that is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, v is an integer that is 3, 4, 5, 6, or 7. In some embodiments, v is an integer that is 6.
[0052] In some embodiments, PNA1 is the peptide nucleic acid sequence. In some embodiments, PNA2 is the peptide nucleic acid sequence.
[0053] In some embodiments, L1 is the linker group. In some embodiments, the linker group of L1 is cleavable. In some embodiments, the linker group of L1 is non-cleavable. In some embodiments, the linker group of L1 is a peptide sequence. In some embodiments, the linker group of L1 is a polyamine sequence. In some embodiments, the linker group of L1 is a polyamide sequence. In some embodiments, the linker group of L1 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L1 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L1 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L1 is a residue of oxalic acid. In some embodiments, the linker group of L1 is a residue of succinic acid. In some embodiments, the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L1 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L1 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L1 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)- In some embodiments, the linker group of L1 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L1 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L1 is -NH(CH2)5C(0)-. In some embodiments, the linker group of L1 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L1 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L1 is -NH(CH2)5C(O)NH(Ctl2)2-(/I-arginine)-(7J-arginine)- (D)-arginine). In some embodiments, the linker group of L1 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L1 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L1 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH2O)2CH2C(0)-.
In some embodiments, the linker group of L1 is - NN(CH2CH2O)2CH2C(O-) NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L1 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group of L1 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L1 is a peptide sequence that is -Lys-.
[0054] In some embodiments, L2 is the linker group. In some embodiments, the linker group of L2 is cleavable. In some embodiments, the linker group of L2 is non-cleavable. In some embodiments, the linker group of L2 is a peptide sequence. In some embodiments, the linker group of L2 is a polyamine sequence. In some embodiments, the linker group of L2 is a polyamide sequence. In some embodiments, the linker group of L2 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L2 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L2 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L2 is a residue of oxalic acid. In some embodiments, the linker group of L2 is a residue of succinic acid. In some embodiments, the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-. In some embodiments, the linker group of L2 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L2 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group ofL2 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L2 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L2 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L2 is -NH(CH2)5C(O)-. In some embodiments, the linker group of L2 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L2 is -NH(CH2)5C(O)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L2 is -NH(CH2)5C(0)NH(CH2)2-(/I-arginine)-(yJ-arginine)- (D -arginine). In some embodiments, the linker group of L2 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L2 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L2 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
In some embodiments, the linker group of L2 is -NH(CH2CH20)2CH2C(0)- NH(CH2CH2O)2CH2C(0)-Arg-. In some embodiments, the linker group of L2 is - NH(CH2CH2O)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group ofL2 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L2 is a peptide sequence that is -Lys-.
[0055] In some embodiments, L3 is the linker group. In some embodiments, the linker group of L3 is cleavable. In some embodiments, the linker group of L3 is non-cleavable. In some embodiments, the linker group of L3 is a peptide sequence. In some embodiments, the linker group of L3 is a polyamine sequence. In some embodiments, the linker group of L3 is a polyamide sequence. In some embodiments, the linker group of L3 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L3 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L3 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L3 is a residue of oxalic acid. In some embodiments, the linker group of L3 is a residue of succinic acid. In some embodiments, the linker group of L3 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L3 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group ofL3 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L3 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L3 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L3 is -NH(CH2)5C(0)-. In some embodiments, the linker group of L3 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L3 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L3 is -M I(CI I )^C(0)NI I(CI I;)>-(/J-arginine)-(7J-arginine)- (D-arginine). In some embodiments, the linker group of L3 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L3 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L3 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L3 is -MIlGLhCbhO^CbhCXO)- NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L3 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group ofL3 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L3 is a peptide sequence that is -Lys-.
[0056] In some embodiments, L4 is the linker group. In some embodiments, the linker group of L4 is cleavable. In some embodiments, the linker group of L4 is non-cleavable. In some embodiments, the linker group of L4 is a peptide sequence. In some embodiments, the linker group of L4 is a polyamine sequence. In some embodiments, the linker group of L4 is a polyamide sequence. In some embodiments, the linker group of L4 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L4 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L4 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L4 is a residue of oxalic acid. In some embodiments, the linker group of L4 is a residue of succinic acid. In some embodiments, the linker group of L4 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(1SIH2)C(0)-. In some embodiments, the linker group of L4 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L4 is NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-Lys-. In some embodiments, the linker group of L4 is NHCH(C00H)C(CH3)2S-SCH2CH(1SIH2)C(0)-Lys-. In some embodiments, the linker group of L4 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L4 is -NH(CH2)5C(0)-. In some embodiments, the linker group of L4 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)MI(CH2)2C(0)-. In some embodiments, the linker group of L4 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L4 is -MI(CH2)5C(0)NH(CH2)2-(//-arginine)-(/J-arginine)- (77-arginine). In some embodiments, the linker group of L4 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L4 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L4 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L4 is -NH(CH2CH20)2CH2C(0)- NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L4 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group ofL4 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L4 is a peptide sequence that is -Lys-.
[0057] In some embodiments, L5 is the linker group. In some embodiments, the linker group of L5 is cleavable. In some embodiments, the linker group of L5 is non-cleavable. In some embodiments, the linker group of L5 is a peptide sequence. In some embodiments, the linker group of L5 is a polyamine sequence. In some embodiments, the linker group of L5 is a polyamide sequence. In some embodiments, the linker group of L5 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L5 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L5 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L5 is a residue of oxalic acid. In some embodiments, the linker group of L5 is a residue of succinic acid. In some embodiments, the linker group of L5 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L5 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group ofL5 is NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-Lys-. In some embodiments, the linker group of L5 is NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-Lys-. In some embodiments, the linker group of L5 is -Arg-NH(CH2)5C(0)-. In some embodiments, the linker group of L5 is -NH(CH2)5C(0)-. In some embodiments, the linker group of L5 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L5 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L5 is -NH(CH2)5C(0)NH(Ctl2)2-(//-arginine)-(7J-arginine)- (Z)-arginine). In some embodiments, the linker group of L5 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L5 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L5 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
In some embodiments, the linker group of L5 is -NHlGhhChkO^ChhClO)- NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L5 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group of L5 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L5 is a peptide sequence that is -Lys-.
[0058] In some embodiments, L6 is the linker group. In some embodiments, the linker group of L6 is cleavable. In some embodiments, the linker group of L6 is non-cleavable. In some embodiments, the linker group of L6 is a peptide sequence. In some embodiments, the linker group of L6 is a polyamine sequence. In some embodiments, the linker group of L6 is a polyamide sequence. In some embodiments, the linker group of L6 is a residue of an omega- amino fatty acid. In some embodiments, the linker group of L6 is a residue of an omega-amino caproic acid. In some embodiments, the linker group of L6 is a residue of a dicarboxylic acid. In some embodiments, the linker group of L6 is a residue of oxalic acid. In some embodiments, the linker group of L6 is a residue of succinic acid. In some embodiments, the linker group of L6 is a peptide sequence that is -Glu-Val- Citrulline-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. In some embodiments, the linker group of L6 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-. In some embodiments, the linker group of L6 is NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-Lys-. In some embodiments, the linker group of L6 is NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-Lys-. In some embodiments, the linker group of L6 is -Arg-NH(CH3)2C(0)-. In some embodiments, the linker group of L6 is -NH(CH2)5C(0)-. In some embodiments, the linker group of L6 is - NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-. In some embodiments, the linker group of L6 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0). In some embodiments, the linker group of L6 is -NH(CH2)5C(0)NH(CH2)2-(/9-arginine)-(/9-arginine)- (79-arginine). In some embodiments, the linker group of L6 is -NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L6 is -NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L6 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-. In some embodiments, the linker group of L6 is -NH(CH2CH20)2CH2C(0)- NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L6 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-. In some embodiments, the linker group ofL6 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-. In some embodiments, the linker group of L6 is a peptide sequence that is -Lys-.
[0059] In some embodiments, the structure is:
Figure imgf000031_0001
wherein: the number of units with variables defined independently is at least 11;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; and
C-Terminus is OH, OMe, NH2, or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
[0060] In some embodiments, the structure is:
Figure imgf000032_0002
[0061] In some embodiments, the structure binds to a sequence of nucleic acids encoding a gene associated with a neurodegenerative disease phenotype. In some embodiments, the structure binds to a mRNA sequence transcribed from a gene associated with a neurodegenerative disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of the gene. In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease (HD) phenotype. In some embodiments, the HD gene is a non-wild type HD gene. In some embodiments, the non-wild type HD gene differs from a wild type HD gene in a repeat expansion mutation.
[0062] In some embodiments, the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG)n (SEQ ID NO: 135) or (CTG)n (SEQ ID NO: 182), wherein each n is independently an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1-20, an integer from 1-15, or an integer from 1-10. In some embodiments, the structure binds to the mRNA sequence at the subsequence that is (CAG)n (SEQ ID NO: 135). In some embodiments, the structure binds to the DNA sequence at the subsequence that is (CTG)n (SEQ ID NO: 182).
[0063] In some embodiments, the number of units with variables defined independently is 11- 1,000. In some embodiments, the number of units with variables defined independently is 11- 100. In some embodiments, the number of units with variables defined independently is 11-50. In some embodiments, the number of units with variables defined independently is 11, 12, 13,
Figure imgf000032_0001
[0064] In some embodiments, each R1 is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2- yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent-l-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl. In some embodiments, each R1 is independently alkyl that is substituted. In some embodiments, each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group. In some embodiments, each alkyl that is substituted is independently hydroxymethyl, 1- hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4-aminobut-l-yl, 3-aminoprop-l-yl, 1- H-imidazoM-ylmethyl, I -H-indol-3-ylmethyl, benzyl, 4-hydroxyphen-l-ylmethyl, 2- carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3 -guani dinoprop- 1-yl, 4-guanidinobut-l-yl, 2- carbamoyleth-l-yl, or 3 -carbarn oylprop- 1-yl.
[0065] In some embodiments, each R1 is independently H, hydroxylmethyl, or 4-guanidinobut- l-yl. In some embodiments, at least one iteration of R1 is hydroxylmethyl. In some embodiments, at least a third of the iterations of R1 are hydroxylmethyl. In some embodiments, at least half the iterations of R1 are hydroxylmethyl.
[0066] In some embodiments, each Ralpha is independently alkyl that is unsubstituted. In some embodiments, each alkyl that is unsubstituted is independently methyl, ethyl, prop- 1-yl, prop-2- yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent-l-yl. In some embodiments, each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, or but-2-yl.
[0067] In some embodiments, each Ralpha is independently alkyl that is substituted. In some embodiments, each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group. In some embodiments, each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4-aminobut- 1 -yl, 3- aminoprop-l-yl, 1 -H-imidazol-4-yl methyl, I -H-indol-3-ylmethyl, benzyl, 4-hydroxyphen-l- ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guani dinoprop- 1-yl, 4-guanidinobut- l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[0068] In some embodiments, each Ralpha is independently H, 3-guanidinoprop-l-yl, or 4- guanidinobut-l-yl. In some embodiments, at least one iteration of Ralpha is 3-guanidinoprop-l-yl. In some embodiments, at least a third of the iterations of Ralpha are 3-guanidinoprop-l-yl. In some embodiments, at least half the iterations of Ralpha are 3-guanidinoprop-l-yl.
[0069] In some embodiments, of the units with variables defined independently, counting from N -Terminus, the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty- second units, independently if present, are each 3-guanidinoprop-l-yl.
[0070] In some embodiments, at least a third of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, at least half of the R2 groups in the structure are methyl substituted with a heterocycle. In some embodiments, the heterocycles of the R2 groups are nucleobases or analogues of nucleobases. In some embodiments, at least one of the heterocycles of the R2 groups is a divalent nucleobase. In some embodiments, the heterocycles of the R2 groups are divalent nucleobases.
[0071] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000034_0001
[0072] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000034_0002
[0073] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000034_0003
[0074] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000034_0006
[0075] In some embodiments, each R2 is independently: methyl,
Figure imgf000034_0004
[0076] In some embodiments, each R2 is independently: methyl,
Figure imgf000034_0005
[0077] In some embodiments, each R2 is independently: methyl,
Figure imgf000035_0001
[0078] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000035_0002
[0079] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000035_0003
[0080] In some embodiments, the heterocycles of the R2 groups are each independently:
Figure imgf000035_0004
[0081] In some embodiments, each R2 is independently: methyl,
Figure imgf000035_0005
[0082] In some embodiments, each R2 is independently: methyl,
Figure imgf000035_0006
[0083] In some embodiments, each R2 is independently: methyl,
Figure imgf000036_0001
[0085] In some embodiments, each R2 is independently:
Figure imgf000036_0002
[0086] In some embodiments, each R2 is independently:
Figure imgf000036_0003
[0087] In some embodiments, N -Terminus is H.
[0088] In some embodiments, N-Terminus is acyl. In some embodiments, A'-Terminus is the biological agent. In some embodiments, the biological agent is a vitamin E group. In some embodiments, the biological agent is an O-bound tocopherol group. In some embodiments, C- Terminus is NH2. In some embodiments, C-Terminus is -Pro-Lys-Lys-Lys-Arg-Lys-Val- NH2. In some embodiments, the neurodegenerative disease is Huntington's disease.
[0089] In some embodiments, the disclosure provides a compound comprising a structure that is:
Figure imgf000037_0001
wherein: the number of units with variables defined independently is at least 11;
N-Terminus is H, acyl, a group that together with the nitrogen atom to which N-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, OMe, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0090] In some embodiments, the structure is:
Figure imgf000038_0001
wherein: the number of units with variables defined independently is at least 11; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; and
C-Terminus is OH, OMe, NH2, or a peptide sequence, or a pharmaceutically-acceptable salt or ionized form thereof.
[0091] In some embodiments, the disclosure provides a compound comprising a structure that is:
Figure imgf000038_0002
wherein: the number of units with variables defined independently is at least 3; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; C-Terminus is OH, OMe, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent; wherein at least one of PEP 1 and PEP2 is a peptide sequence of at least three amino acid residues,
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0092] In some embodiments, the disclosure provides a compound comprising a structure that is:
Figure imgf000039_0001
wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero; 77-Terminus is H, acyl, a group that together with the nitrogen atom to which 77-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a hydroxyalkyl group; each R4 is independently R2; each R5 is independently a group that is not hydroxyalkyl; each R6 is independently R2; each R7 is independently alkyl that is unsubstituted or substituted or H; each R8 is independently R2, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha2 is independently alkyl that is unsubstituted or substituted or H; each Ralpha3 is independently alkyl that is unsubstituted or substituted or H; each Ralpha 4 is inaldpheap1endently alkyl that is unsubstituted or substituted or H;
C-Terminus is OH, OMe, or MH;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[0093] In some embodiments, the first number of units with variables defined independently is 3-1,000. In some embodiments, the first number of units with variables defined independently is 3-100. In some embodiments, the first number of units with variables defined independently is 3-50. In some embodiments, the first number of units with variables defined independently is 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the first number of units with variables defined independently is at least 11. In some embodiments, the first number of units with variables defined independently is 11-
I,000 In some embodiments, the first number of units with variables defined independently is
11-100. In some embodiments, the first number of units with variables defined independently is 11-50. In some embodiments, the first number of units with variables defined independently is
II, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[0094] In some embodiments, the second number of units with variables defined independently is 3-1,000. In some embodiments, the second number of units with variables defined independently is 3-100. In some embodiments, the second number of units with variables defined independently is 3-50. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
[0095] In some embodiments, the third number of units with variables defined independently is 3-1,000. In some embodiments, the third number of units with variables defined independently is 3-100. In some embodiments, the third number of units with variables defined independently is 3-50. In some embodiments, the third number of units with variables defined independently is
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
30. In some embodiments, the third number of units with variables defined independently is at least 11. In some embodiments, the third number of units with variables defined independently is 11-1,000. In some embodiments, the third number of units with variables defined independently is 11-100. In some embodiments, the third number of units with variables defined independently is 11-50. In some embodiments, the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. [0096] In some embodiments, each R3 is hydroxymethyl. In some embodiments, each R5 is H. [0097] In some embodiments, the disclosure provides a compound comprising a repeating unit of formula:
Figure imgf000041_0001
wherein: each R1 is independently a hydroxyalkyl group; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a group that is not hydroxy alkyl; each R4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; and each Ralpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
[0098] In some embodiments, the disclosure provides a compound comprising:
1) a region that comprises a structure that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the region that comprises the structure that interferes with expression of the gene associated with a neurodegenerative disease phenotype, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000042_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O- alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O- alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[0099] In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease phenotype. In some embodiments, the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype. In some embodiments, the structure binds to a DNA sequence transcribed from a gene associated with a Huntington’s disease phenotype. In some embodiments, the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of the Huntington’s disease gene. In some embodiments, the Huntington’s Disease gene is a non-wild type Huntington’s disease gene. In some embodiments, the non-wild type Huntington’s disease gene differs from a wild type Huntington’s disease gene in a repeat expansion mutation.
[00100] In some embodiments, the structure binds to a RNA (e.g., mRNA) sequence that contains a subsequence that is (CAG)n (SEQ ID NO: 135), wherein n is an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1-20, an integer from 1-15, or an integer from 1-10. In some embodiments, the structure binds to the mRNA sequence at the subsequence that is (CAG)n (SEQ ID NO: 135). [00101] In some embodiments, the structure binds to a DNA sequence that contains a subsequence that is (CTG)n (SEQ ID NO: 182), wherein n is an integer from 1-100, an integer from 1-50, an integer from 1-40, an integer from 1-30, an integer from 1-25, an integer from 1- 20, an integer from 1-15, or an integer from 1-10. In some embodiments, the structure binds to the DNA sequence at the subsequence that is (CTG)n (SEQ ID NO: 182).
[00102] In some embodiments, the disclosure provides a compound comprising:
1) a region that comprises a structure that interferes with expression of a gene associated with a Huntington’s disease phenotype; and
2) connected to the region that comprises the structure that interferes with expression of a gene associated with a Huntington’s disease phenotype, a compound comprising a repeating unit, wherein the repeating unit comprises: a) a guanidino group; b) a nitrogen atom that is bound to a -C(0)Me group and a -CH2C(0)- group; and c) a chain of carbon atoms, wherein the guanidino group is attached to the chain of carbon atoms at a first point of attachment; wherein the nitrogen atom is attached to the chain of carbon atoms at a second point of attachment; and wherein the first point of attachment and the second point of attachment are separated by 3-12 carbon atoms, or a pharmaceutically-acceptable salt or ionized form thereof. [00103] In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00104] In some embodiments, the disclosure provides a compound comprising:
1) a region that comprises a structure that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the region that comprises the structure that interferes with expression of a gene associated with a neurodegenerative disease phenotype, a compound of formula:
Figure imgf000044_0001
, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN);
E1 is a chemical moiety;
E2 is a chemical moiety; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000, or a pharmaceutically-acceptable salt or ionized form thereof.
[00105] In some embodiments, the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00106] In some embodiments, the number of units with variables defined independently is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein: a first unit is present or absent, and in the first unit:
Figure imgf000045_0001
a second unit is present or absent, and in the second unit:
Figure imgf000045_0002
a third unit is present, and in the third unit:
Figure imgf000045_0003
a fourth unit is present, and in the fourth unit:
Figure imgf000045_0004
a fifth unit is present, and in the fifth unit:
Figure imgf000045_0005
a sixth unit is present, and in the sixth unit:
Figure imgf000046_0001
a seventh unit is present, and in the seventh unit:
Figure imgf000046_0002
an eighth unit is present, and in the eighth unit:
Figure imgf000046_0003
a ninth unit is present, and in the ninth unit:
Figure imgf000046_0004
a tenth unit is present, and in the tenth unit:
Figure imgf000046_0005
an eleventh unit is present, and in the eleventh unit:
Figure imgf000046_0006
a twelfth unit is present, and in the twelfth unit:
Figure imgf000047_0001
a thirteenth unit is present, and in the thirteenth unit:
Figure imgf000047_0002
a fourteenth unit is present, and in the fourteenth unit:
Figure imgf000047_0003
a fifteenth unit is present or absent, and in the fifteenth unit:
Figure imgf000047_0004
a sixteenth unit is present or absent, and in the sixteenth unit:
Figure imgf000047_0005
a seventeenth unit is present or absent, and in the seventeenth unit:
Figure imgf000048_0001
an eighteenth unit is present or absent, and in the eighteenth unit:
Figure imgf000048_0002
nineteenth unit is present or absent, and in the nineteenth unit:
Figure imgf000048_0003
a twentieth unit is present or absent, and in the twentieth unit:
Figure imgf000048_0004
an twenty-first unit is present or absent, and in the twenty-first unit:
Figure imgf000048_0005
a twenty-second unit is present or absent, and in the twenty-second unit:
R1 is H or -CH2OH; and R2 i iss
Figure imgf000048_0006
a twenty-third unit is present or absent, and in the twenty-third unit:
Figure imgf000049_0001
an twenty-fourth unit is present or absent, and in the twenty-fourth unit:
Figure imgf000049_0002
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
Figure imgf000049_0003
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
Figure imgf000049_0004
[00107] In some embodiments, of the units with variables defined independently, counting from N -Terminus, the first unit, the fourth unit, the seventh unit, the tenth unit, the thirteenth unit, the sixteenth unit, the nineteenth unit, the twenty-second unit, and the twenty-fifth unit, independently if present, each have
Figure imgf000049_0005
[00108] In some embodiments, wherein of the units with variables defined independently, counting from N -Terminus, the second unit, the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty -third unit, and the twenty- sixth unit, independently if present, each have
Figure imgf000050_0001
[00109] In some embodiments, wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty-fourth unit, independently if present, each have
Figure imgf000050_0002
atR .
[00110] In some embodiments, wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty-fourth unit, independently if present, each have
Figure imgf000050_0003
[00111] In some embodiments, the number of units with variables defined independently is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein: a first unit is present or absent, and in the first unit:
Figure imgf000050_0004
a second unit is present or absent, and in the second unit:
Figure imgf000050_0005
a third unit is present, and in the third unit:
Figure imgf000051_0001
a fourth unit is present, and in the fourth unit:
Figure imgf000051_0002
a fifth unit is present, and in the fifth unit:
Figure imgf000051_0003
a sixth unit is present, and in the sixth unit:
Figure imgf000051_0004
a seventh unit is present, and in the seventh unit:
Figure imgf000051_0005
an eighth unit is present, and in the eighth unit:
Figure imgf000052_0001
a ninth unit is present, and in the ninth unit:
Figure imgf000052_0002
a tenth unit is present, and in the tenth unit:
Figure imgf000052_0003
an eleventh unit is present, and in the eleventh unit:
Figure imgf000052_0004
a twelfth unit is present, and in the twelfth unit:
Figure imgf000052_0005
a thirteenth unit is present, and in the thirteenth unit:
Figure imgf000053_0001
a fourteenth unit is present, and in the fourteenth unit:
Figure imgf000053_0002
a fifteenth unit is present or absent, and in the fifteenth unit:
Figure imgf000053_0003
a sixteenth unit is present or absent, and in the sixteenth unit:
Figure imgf000053_0004
a seventeenth unit is present or absent, and in the seventeenth unit:
Figure imgf000053_0005
an eighteenth unit is present or absent, and in the eighteenth unit:
Figure imgf000054_0001
a nineteenth unit is present or absent, and in the nineteenth unit:
Figure imgf000054_0002
a twentieth unit is present or absent, and in the twentieth unit:
Figure imgf000054_0003
an twenty-first unit is present or absent, and in the twenty-first unit:
Figure imgf000054_0004
a twenty-second unit is present or absent, and in the twenty-second unit:
Figure imgf000054_0005
a twenty-third unit is present or absent, and in the twenty-third unit:
Figure imgf000055_0001
an twenty-fourth unit is present or absent, and in the twenty-fourth unit:
Figure imgf000055_0002
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
Figure imgf000055_0003
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
Figure imgf000055_0004
[00112] In some embodiments, in the second unit, the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty -third unit, and the twenty-sixth unit,
Figure imgf000055_0005
some embodiments, in the second unit, the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty-third unit, and the twenty-sixth unit,
Figure imgf000056_0001
[00113] In some embodiments, in the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, and the twenty -fourth unit, R2 is
Figure imgf000056_0002
some embodiments, in the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty-fourth
Figure imgf000056_0003
[00114] In some embodiments, in each of the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty sixth unit, R1 is hydrogen.
[00115] In some embodiments, in each of the fourth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty-second unit, the twenty -third unit, the twenty-fifth unit, and the twenty-sixth unit, R1 is hydrogen.
[00116] In some embodiments, in each of the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty-fifth unit, R1 is -CH2OH.
[00117] In some embodiments, in each of the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, the twenty -fourth unit, R1 is -CH2OH.
[00118] In some embodiments, in each of the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty-fifth unit, Ralphais -CH2OH. [00119] In some embodiments, in each of the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, the twenty -fourth unit, Ralpha is -CH2OH.
[00120] In some embodiments, in each of the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty-fifth unit, Ralphais 3-guanidino- prop-l-yl.
[00121] In some embodiments, in each of the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, the twenty-fourth unit, Ralpha is 3-guanidino-prop-l-yl.
[00122] In some embodiments, in each of the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, the twenty-fourth unit, R1 is 4-guanidino-but-l-yl.
[00123] In some embodiments, in each of the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty-third unit, and the twenty-fifth unit, R1 is 4-guanidino-but- l-yl.
[00124] Two-dimensional molecular structures of selected compounds of the disclosure are provided in Figures 4-13. FIG. 4 illustrates the structure of Compound 1. FIG. 5 illustrates the structure of Compound 2. FIG. 6 illustrates the structure of Compound 16. FIG. 7 illustrates the structure of Compound 52. FIG. 8 illustrates the structure of Compound 57. FIG. 9 illustrates the structure of Compound 58. FIG. 10 illustrates the structure of Compound 59. FIG. 11 illustrates the structure of Compound 75. FIG. 12 illustrates the structure of Compound 76.
FIG. 13 illustrates the structure of Compound 77.
[00125] FIG. 3 depicts nonlimiting examples of oligonucleotide backbones, where R is a nucleobase (e g. natural, modified, or non-natural nucleobases), or hydrogen. One or more oligonucleotide residues of a compound of the disclosure may be independently replaced with a residue comprising an alternative oligonucleotide backbone bearing an identical nucleobase. Nonlimiting examples of oligonucleotide backbones suitable for use in the present disclosure include phosphorothioate deoxyribonucleic acid (PS-DNA), boranophosphate DNA, alpha-, beta- constrained nucleic acid (a,β-CnA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'- fluororibonucleic acid (2'-F-RNA), 2'-fluoroarabinonucleic acid (2'-F-ANA), sulfonyl-linked nucleic acid, methylene(methylimino) (MMI) linked, formacetal-linked nucleic acid, threose nucleic acid (TNA), 2'-methoxyribonucleic acid (2'-OMe-RNA), 2'-0-(2- methoxyethyl)ribonucleic acid (2'-MOE-RNA), unlocked nucleic acid (UNA), 2'-0,4'-C- ethylene-bridged nucleic acid (ENA), 2'-0,4'-C-propylene bridged nucleic acid (PrNA), bridged nucleic acids (e.g., 2',4'-BNAC0C, 2',4'-BNANC[NH], 2',4'-BNANC[NMe], 3',4'-BNA), locked nucleic acid (LNA), bicylco[3.2.1]nucleic acid, (5)-constrained ethyl nucleic acid ((S)-cEt), hexitol nucleic acid (HNA), homo-deoxyribonucleic acid (hNDA), phosphorodiamidate morpholino oligomer (PMO), peptide nucleic acid (PNA), cyclohexene nucleic acid (CeNA), benzene phosphate backbone, tricyclo-DNA(tcDNA), glycol nucleic acid (GNA), and epimers and diastereomers thereof.
[00126] A compound of the disclosure (e.g. a peptide nucleic acid) can be conjugated to one or more polypeptides, such as a cell penetrating peptide, nuclear localization sequence, or other polypeptide that can facilitate uptake or cellular intake. Nonlimiting examples of cell- penetrating peptides include SV40 NLS (SEQ ID NO: 1: PKKKRKV), c-Myc NLS (SEQ ID NO: 2: PAAKRVKLD), nuleoplasmin (SEQ ID NO. 3: KRPAATKKAGQAKKKL), NF-Kb NLS (SEQ ID NO: 4: V QRKRQKLMP), TFIIE beta NLS (SEQ ID NO: 5: SKKKKTKV), Oct- 6 NLS (SEQ ID NO: 6: GRKRKKRT), HATF-3 NLS (SEQ ID NO: 7: ERKKRRRE), SDC3 NLS (SEQ ID NO: 8: FKKFRKF), DPV3 (SEQ ID NO: 9: RKKRRRESRKKRRRES), DPV6 (SEQ ID NO: 10: GRPRE S GKKRKRKRLKP), DPV7 (SEQ ID NO: 11 : GKRKKKGKLGKKRDP), DPV7b (SEQ ID NO: 12: GKRKKKGKLGKKRPRSR), DPV3/10 (SEQ ID NO: 13: RKKRRRESRRARRSPRHL), DPV10/6 (SEQ ID NO: 14: SRRARRSPRESGKKRKRKR), DPV1047 (SEQ ID NO: 15: VKRGLKLRHVRPRVTRMDV), DPV 10 (SEQ ID NO: 16: SRRARRSPRHLGSG), DPV15 (SEQ ID NO: 17:
LRRERQ SRLRRERQ SR), DPV15b (SEQ ID NO: 18: GAYDLRRRERQ SRLRRRERQSR), HIV-1 Tat (SEQ ID NO: 19: RKKRRQRRR), FHV coat (SEQ ID NO: 20: RRRRNRTRRNRRRVR), HIV-1 Rev (SEQ ID NO: 21: TRQARRNRRRRWRERQR), HTLV- II Rex (SEQ ID NO: 22: TRRQRTRRARRNR), BMV Gag (SEQ ID NO: 23: KMTRAQRRAAARRNRWTAR, P22 N (SEQ ID NO: 24 NAKTRRHERRRKLAIER), lN(1- 22) (SEQ ID NO: 25: MDAQTRRRERRAEKQAQWKAAN), f21N(12-29) (SEQ ID NO: 26:
T AKTRYK ARRAEL1AERR), Yeast Prp6 (SEQ ID NO: 27: TRRNKRNRIQEQLNRK), Protamine 1 (SEQ ID NO: 28: PRRRRS S SRP VRRRRRPRV SRRRRRRGGRRRR), Human cJun (SEQ ID NO: 29: RIKAERKRMRNRIAASKSRKRKLERIAR), Human cFos (SEQ ID NO: 30: KRRIRRERNKMAAAKSRNRRRELTDT), Yeast GCN4 (SEQ ID NO: 31 : KRARNTEAARRSRARKLQRMKQ), Penetratin (SEQ ID NO: 32:
RQnCIWF QNRRMKWKK), Islet-1 (SEQ ID NO: 33: RVIRVWF QNKRCKDKK), Fushi-tarazu (SEQ ID NO: 34:
SKRTRQT YTRY QTLELEKEFHFNRYITRRRRIDIANAL SL SERQDCIWF QNRRMKSKKDR ), Engrailed-2 (SEQ ID NO: 35: SQDCIWF QNKRAKDCK), HoxA-13 (SEQ ID NO: 36: RQ VTIWF QNRRVKEKK), Knotted- 1 (SEQ ID NO: 37: KQINNWFINQRKRHWK), PDX-1 (SEQ ID NO: 38: RHIKIWFQNRRMKWKK), MPG (SEQ ID NO: 39: GLAFLGFLGAAGSTMGAWSQPKKKRKV), Bac7 (SEQ ID NO: 40: RRIRPRPPRLPRPRPRPLPFPRPG), S413-PVrev (SEQ ID NO: 41: ALWKTLLKKVLKAPKKKRKV), HRSV (SEQ ID NO: 42: RRIPNRRPRR). L-2 (SEQ ID NO: 43: HARIKPTFRRLKWKYKGKFW), Melittin (SEQ ID NO: 44:
GIGAVLKVLTT GLP AL1SWIKRKRQQ), SynBl (SEQ ID NO: 45: RGGRLSYSRRRFSTSTGR), IVV-14 (SEQ ID NO: 46: KLWMRWY SPTTRRY G), AIP6 (SEQ ID NO: 47: RLRWR), CAYH (SEQ ID NO: 48: CAYHRLRRC), SVM4 (SEQ ID NO:
49: LYKKGPAKKGRPPLRGWFH), SVM3 (SEQ ID NO: 50: KGTYKKKLMRIPLKGT), SVM2 (SEQ ID NO: 51: RASKRDGSWVKKLHRILE), Buforin 2 (SEQ ID NO: 52:
TRS SRAGLQWPVGRVHRLLRK), SVM1 (SEQ ID NO: 53: FKIYDKKVRTRVVKH), SAP (SEQ ID NO: 54: VRLPPPVRLPPPVRLPPP), 435b (SEQ ID NO: 55: GPFHFYQFLFPPV), Peptl (SEQ ID NO: 56: PL1LLRLLRGQF ), YTA2 (SEQ ID NO: 57:
YT AIAW VK AFIRKLRK), Pep-1 (SEQ ID NO: 58: KETWWETWWTEWSQPKKRKV), EB-1 (SEQ ID NO: 59: L1RLW SHL1HIWFQNRRLKWKKK), Pyrrho-coricin (SEQ ID NO: 60: VDKGSYLPRPTPPRPIYNRN), 439a (SEQ ID NO: 61: GSPW GLQHHPPRT), MAP (SEQ ID NO: 62: KLALKALKALKAALKLA), Bip (1) (SEQ ID NO: 63: IPALK), Bip (2) (SEQ ID NO: 64: VPALR), pVEC (SEQ ID NO: 65: LL1ILRRRIRKQAHAHSK), YTA4 (SEQ ID NO: 66: IAWVKAFIRKLRKGPLG), K-FGF+NLS (SEQ ID NO: 67:
AA VLLP VLL AAP V QRKRQKLP), HN-1 (SEQ ID NO: 68: TSPLNIHNGQKL), Bip (3) (SEQ ID NO: 69: VPTLK), Bip (4) (SEQ ID NO: 70: VSALK), VT5 (SEQ ID NO: 71 : DPKGDPKGVTVTVTVTVTGKGDPKPD), Transportan 10 (SEQ ID NO: 72: AGYLLGKINLKALAALAKKIL), SAP(E) (SEQ ID NO: 73: VELPPPYELPPPVELPPP), CADY (SEQ ID NO: 74: GLWRALWRLLRSLWRLLWRA), PreS2-TLM (SEQ ID NO: 75: PLSSIFSRIGDP), R/W (SEQ ID NO: 76: RRWWRRWRR), Xentry (SEQ ID NO: 141 : LCLRPVG), or combinations of any of the preceding.
[00127] In some embodiments, a compound of the disclosure is conjugated to a peptide that targets specific tissue, such as a muscle-targeting peptides. Suitable muscle targeting peptides can include, for example, MSP1 (SEQ ID NO: 77: AKASSLNIA), MSP2 (SEQ ID NO: 78: ASSLNIA), and A2G80 (SEQ ID NO: 79: VQLRNGFPYFSY).
[00128] In some embodiments, a compound of the disclosure is conjugated to a peptide that targets brain tissue. Suitable brain targeting peptides can include, for example, SEQ ID NO: 142: C(&)LS SRLD AC(&), SEQ ID NO: 143: C(&)AGALC(&)Y, SEQ ID NO: 144: C(&)LEVSRKNC(&), SEQ ID NO: 145: C(&)TSTSAPYC(&), SEQ ID NO: 146: c(&)MPRLRGC(&), and SEQ ID NO: 147: T GNYK ALHPHN G.
[00129] Other peptides suitable for conjugation with a compound of the disclosure include transferrin receptor binders, such as THR (SEQ ID NO: 80: THRPPMWSPVWP) and HAI (SEQ ID NO: 81: HAIYPRH), as well as peptides that bind transferrin receptor-transferrin complex, such as CRT (SEQ ID NO: 82: C(&)RTIGPSVC(&)).
[00130] Retro-enantio analogues of any peptide disclosed herein are also suitable for conjugation to a compound of the present disclosure. A retro-enantio analogue can mimic the natural function of a corresponding parent peptide while exhibiting increased resistance to degradation. A retro-enantio analogue includes a peptide analogue where, relative to a parent peptide, both the linear peptide sequence and alpha-carbon chirality are inverted. For example, a retro-enantio analogue of THR (SEQ ID NO: 80: THRPPMWSPVWP) can be THRre (SEQ ID NO: 83: pwvpswmpprht), and a retro-enantio analogue of HAI (SEQ ID NO: 81: HAIYPRH) can be HAIre (SEQ ID NO: 84: hrpyiah), where lowercase one letter codes denote D-amino acid residues.
[00131] Enantiomers of any peptide disclosed herein are also contemplated, which enantiomers can include, for example, D-THR (SEQ ID NO: 85: thrppmwspvwp).
[00132] Other peptides suitable for conjugation with a compound of the disclosure include peptides consisting of or comprising sequences such as RFQILYR (SEQ ID NO: 86), RYQFL1R (SEQ ID NO: 87), RIQFL1R (SEQ ID NO: 88), RRWQW (SEQ ID NO: 89), GWWG (SEQ ID NO: 90), GFWFG (SEQ ID NO: 91), and GRKKRRQRRRPQ (SEQ ID NO: 92). Peptides comprising repeating units of charged residues are also contemplated, such as sequences comprising repeating units of contiguous arginine and glycine residues, such as (RG)e where e is from 1 to 50 (SEQ ID NO: 138) (e g. SEQ ID NO: 93: RGRGRGRGRGRGRG), polyarginine comprising from 2 to 100 contiguous arginine residues (SEQ ID NO: 139), (e.g. SEQ ID NO:
94: RRRRRRRRRRRR, and SEQ ID NO: 148: RRRRRRRR), and repeating units of proline- proline-arginine, such as (PPR)f where f is from 2 to 50 (SEQ ID NO: 140) (e g., SEQ ID NO: 95: PPRPPRPPRPPR).
[00133] In some embodiments, a compound of the disclosure is conjugated to a sequence derived from HIV-1 Tat, which can include, for example, RKKRRQRRR (SEQ ID NO: 19),
Y GRKKRRQRRR (SEQ ID NO: 149), and GRKKRRQ (SEQ ID NO: 150).
[00134] In some embodiments, a compound of the disclosure is complementary to a nucleic acid sequence selected from the group consisting of: CUG, CUGC, CUGCU, CUGCUG,
CUGCUGC, CUGCUGCU, CUGCUGCUG, CUGCUGCUGC (SEQ ID NO: 96), CUGCUGCUGCU (SEQ ID NO: 97), CUGCUGCUGCUG (SEQ ID NO: 98), CUGCUGCUGCUGC (SEQ ID NO: 99), CUGCUGCUGCUGCU (SEQ ID NO: 100), CUGCUGCUGCUGCUG (SEQ ID NO: 101), CUGCUGCUGCUGCUGC (SEQ ID NO: 102), CU GCU GCUGCU GCU GCU (SEQ ID NO: 103), CUGCUGCUGCUGCUGCUG (SEQ ID NO: 104), CU GCU GCU GCU GCU GCU GC (SEQ ID NO: 105), CUGCUGCUGCUGCUGCUGCU (SEQ ID NO: 106), CUGCUGCUGCUGCUGCUGCUG (SEQ ID NO: 107),
CU GCU GCUGCU GCU GCU GCUGC (SEQ ID NO: 108),
CU GCU GCUGCU GCU GCU GCUGCU (SEQ ID NO: 109), and CU GCU GCUGCU GCU GCU GCUGCU G (SEQ ID NO: 110).
[00135] In some embodiments, sequence variants of the sequences described herein are contemplated. A variant typically differs from a sequence specifically disclosed herein in one or more substitutions, deletions, additions and/or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of sequences of the disclosure and evaluating one or more biological activities of the compounds as described herein. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid and/or nucleic acid sequences of the compound. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., modulation of a genetic target.
[00136] Percent (%) sequence identity with respect to a reference polypeptide or oligonucleotide sequence is the percentage of amino acid residues, nucleoside residues, and/or nucleoside analogue residues in a candidate sequence that are identical with residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the degree of sequence identity between two sequences can be determined, for example, by comparing the two sequences using computer programs designed for this purpose, such as global or local alignment algorithms. Non-limiting examples include BLAST, BLAST-2, AL1GN, Megalign (DNASTAR), BLASTp, BLASTn, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline, GAP, BESTFIT, Needle (EMBOSS), Stretcher (EMBOSS), GGEARCH2SEQ, Water (EMBOSS), Matcher (EMBOSS), LAL1GN, SSEARCH2SEQ, or another suitable method, software or algorithm. A global alignment algorithm, such as a Needleman and Wunsch algorithm, can be used to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Default settings can be used. In some embodiments, % sequence identity values can be generated using the sequence comparison computer program AL1GN-2. The AL1GN-2 program can be compiled for use on a UNIX operating system, including digital UNIX V4.0D. Sequences that can be compared by these algorithms include, for example, peptides, oligonucleotides, PNAs, and analogues of any of the foregoing.
[00137] When comparing two compounds that each have nucleobases or amino acid side chains but do not have the same backbone motif, the percent identity determination can be made based on comparison of the nucleobases or amino acid side chains. Residues in the two molecules being compared can be considered to share identity for the purpose of the percent identity analysis if the residues share a common nucleobase or amino acid side chain even if the residues have non-identical backbone structures. For example, Compound 58 and Compound 59 can be considered to share 100% nucleobase sequence identity.
[00138] Compounds disclosed herein can additionally comprise non-proteogenic acids in place of one or more proteogenic amino acids amino acids. Such non-proteogenic acids can include, for example, β-alanine, cystine, cystathionine, lanthionine, t-leucine, norleucine, homonorleucine, ornithine, allothreonine, homocysteine, citrulline, homoserine, isovaline, norvaline, sarcosine, N-ethyl glycine, N-propyl glycine, N-isopropyl glycine, N-methyl alanine, N-ethyl alanine, N-methyl β-alanine, N-ethyl β-alanine, and isoserine.
[00139] Compounds described herein can be associated with modifications of one or more amino acids of the compounds. Non-limiting examples of modifications include phosphorylation, acylation including acetylation and formylation, glycosylation (including N- linked and O-linked), amidation, hydroxylation, alkylation including methylation and ethylation, ubiquitination, addition of pyrrolidone carboxylic acid, formation of disulfide bridges, sulfation, myristoylation, palmitoylation, isoprenylation, farnesylation, geranylation, glypiation, lipoylation and iodination.
[00140] The nucleobases within a PNA subunit can be naturally occurring or non-naturally occurring. Non-limiting examples of nucleobases include adenine, guanine, thymine, cytosine, uracil, pseudoisocytosine, 2-thiopseudoisocytosine, 5-methylcytosine, 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine (or 2,6-diaminopurine), 2-thiouracil, 2-thiothymine, 2- thiocytosine, 5-chlorouracil, 5-bromouracil, 5-iodouracil, 5-chlorocytosine,5-bromocytosine, 5- iodocytosine, 5-propynyl uracil, 5-propynyl cytosine, 6-azo uracil, 6-azo cytosine, 6-azo thymine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7- deazaadenine, 3-deazaguanine, 3-deazaadenine, 7-deaza-8-aza guanine, 7-deaza-8-aza adenine, 5-propynyl uracil and 2-thio-5-propynyl, pyridazin-3(2H)-one (E), pyrimidin-2(lH)-one (P) and 2-aminopyridine (M), and tautomeric forms thereof.
[00141] Compounds disclosed herein can comprise divalent nucleobases. A divalent nucleobase can simultaneously bind specifically to two nucleic acid strands, whether or not the two strands are independent strands, two portions of a single strand (e.g., in a hairpin), or contain mismatches in the sense that at one or more positions within the two strands at the site of binding to the genetic recognition reagents, the bases are not able to base pair according to traditional Watson-Crick base pairing (A-T/U, T/U-A, G-C or C-G). Divalent nucleobases can be incorporated into an oligonucleotide analogue backbone such as those described in FIG. 3 (e.g. PNA monomer), which can then be incorporated into an oligomer of monomers with a desired sequence of nucleobases. TABLE 4 provides example divalent bases and their binding specificities, where R1 is hydrogen or a nitrogen protecting group and X is N or CH.
TABLE 4
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
[00142] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise Attorney Docket No. 54344-731.601 one or more isotopic substitutions. For example, hydrogen can be in any isotopic form, including XH (protium), 2H (D or deuterium), and 3H (T or tritium). Carbon can be in any isotopic form, including 12C, 13C, and 14C. Oxygen can be in any isotopic form, including 16O and 18O.
[00143] Compounds described herein (e.g., PNA subunits and PNA oligomers) can comprise one or more asymmetric centers, and can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods including chiral high-performance liquid chromatography (HPLC), selective crystallization as chiral salts, or in the presence of chiral hosts, or from chiral solvents, and through enrichment using enzymes or chemical processes such as dynamic kinetic resolution. A single isomer can be prepared by asymmetric synthesis. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
Chemical Groups.
[00144] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, hydrocarbyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.
[00145] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl group can be, for example, a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, c46, C47, C48, C49, or C50 group that is substituted or unsubstituted.
[00146] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
[00147] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, secbutyl, and t-butyl.
[00148] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include
-68- Attorney Docket No.54344-731.601 fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups. [00149] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. [00150] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkylnyl or alkynylene group can be internal or terminal. An alkylnyl or alkynylene group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group that is substituted or unsubstituted. [00151] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms. [00152] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy. [00153] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl. [00154] An aryloxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy. [00155] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl. [00156] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy. [00157] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic -69- Attorney Docket No.54344-731.601 (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include nucleobases, pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran. [00158] An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxycarbonyl, and ethoxycarbonyl. [00159] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or an ester group comprises an acyloxy group. A non-limiting example of an acyloxy group, or an ester group, is acetate. [00160] A carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom can form a heterocycle. [00161] A hydrocarbyl group can be any group consisting of carbon and hydrogen atoms, and can include alkyl groups, alkenyl groups, alkynyl groups, and aryl groups. A hydrocaryl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group. [00162] A hydrocarbylcarbonyl group can be a carbonyl group substituted with a hydrocarbyl group, which can be, for example, benzoyl, acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undencanoyl, dodecanoyl, tridencanoyl, myristoyl, pentadecenoyl, palmitoyl, heptadecanoyl, stearoyl, nondecanoyl, arachidoyl, as well as acyl groups derived from saturated, monounsaturated, and polyunsaturated fatty acids, such as myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, elaidoyl, vaccenoyl, linoleoyl, linoelaidoyl, α- linolenoyl, or arachidonoyl. A hydrocarylcarbonyl group can be, for example, a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, or C50 group. [00163] An aminoalkylene group can be an alkyl group substituted with an amino group, such as, for example, aminomethyl, 2-aminoeth-1-yl, 3-aminoprop-1-yl, 2-aminoprop-1-yl, 4- aminobut-1-yl, 3-aminobut-1-yl, 2-aminobut-1-yl, 5-aminopent-1-yl, 4-aminopent-1-yl, 4- aminopent-1-yl, 3-aminopent-1-yl, 2-aminopent-1-yl, a lysine side chain, or an ornithine side chain. [00164] A guanidinoalkylene group can be an alkyl group substituted with a guanidino group, -70- such as, for example, guanidinomethyl, 2-guanidinoeth-l-yl, 3-guanidinoprop-l-yl, 2- guanidinoprop-1-yl, 4-guanidinobut-l-yl, 3-guanidinobut-l-yl, 2-guanidinobut-l-yl, 5- guanidinopenty-1-1, 4-guanidinopent-l-yl, 4-guanidinopent-l-yl, 3-guanidinopent-l-yl, 2- guanidinopent-l-yl, an arginine side chain, or a homoarginine side chain.
[00165] Polypeptides and proteins disclosed herein (including functional portions and functional variants thereof) can comprise synthetic amino acids in place of one or more naturally-occurring amino acids. Such synthetic amino acids can include, for example, aminocyclohexane carboxylic acid, norleucine, a-amino n-decanoic acid, homoserine, S-acetylaminomethyl- cysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4- chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine β-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, indoline-2-carboxylic acid, 1,2, 3, 4-tetrahydroisoquinoline-3 -carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N’-benzyl-N’ -methyl-lysine, N’ ,N’ -dibenzyl -lysine, 6-hydroxylysine, ornithine, a- aminocyclopentane carboxylic acid, a-aminocyclohexane carboxylic acid, a-aminocycloheptane carboxylic acid, a-(2-amino-2-norbomane)-carboxylic acid, a,g-diaminobutyric acid, a,β- diaminopropionic acid, homophenylalanine, and a-tert-butylglycine.
[00166] In some embodiments, a compound of a disclosure bears one or more nitrogen protecting groups. Nonlimiting examples of nitrogen protecting groups include methyl, formyl, ethyl, acetyl, anisyl, benzyl, benzoyl, carbamate, trif!uoroacetyl. diphenylmethyl, triphenylmethyl, , benzyloxymethyl, benzyloxy carbonyl, 2-nitrobenzoy3, t-Boc (tert- butyloxycarbonyl), 4-methylbenzyl, 4-nitrophenyl, 2-chlorobenzyloxycarbony3, 2- bromobenzyloxycarbonyl, 2,4, 5-trichlorophenyl, thioanizyl, thiocresyl, cbz (carbobenzyloxy), p- melhoxybenzyl carbonyl, 9-fluoreiiylraethyloxycarbonyl (Fmoe), pentafluorophenyl, p- methoxybenzyl, 3,4-dimethozybenzyl, p-methoxyphenyl, 4-toluenesuifonyl, p- nitrobenzenesul fonates, 9-fluorenylmetby! oxy carbonyl , 2-nitrophenylsulfenyl, 2, 2, 5,7,8- pentamethyl-chroman-6-su!fonyl, 2-(4-Nitrophenyr)sulfonylethoxycarbonyl (Nsc), 1,1- Dioxobenzo[b]thiophene-2-ylmethyloxy carbonyl (B smoc), 1 , 1 -Dioxonaphtho[ 1 ,2-b]thiophene- 2-methyfoxy carbonyl (a-Nsmoc), 3, 3-Dioxonaphiho[2, 1-b]thiophene-2-methyloxy carbonyl (β- Nsmoc), 1-(4,4-dimethyl-2,6-dioxocyclohex-I-ylidene)-3-methylbutyl (ivDde), 2,7-di-tert- biityl-9-fluorenylmethoxycarbonyl (Fmoc*), 2-monoisooctyl-9-fluorenylmethoxycarbonyl (mio- Fmoc), 2,7-diisooctyl-9-fluorenylmethoxycarbonyl, tetrachlorophthaloyl (TCP), 2-fluon>9- fluorenylmethoxycarbonyl (Fmoc(2F)), 2-[Phenyl(raethyl)sulforao]etbyloxy carbonyl tetrafluoroborate (Pms ), ethanesulfonylethoxycarbonyl (Esc), 2-(4- sul fopheny 3 sulfonyl)ethoxy carbonyl (Sps), N-N-dimethylaminoxy carbonyl (Dmaoc), and p- bromobenzenesulfonyi. Pharmaceutically-acceptable salts.
[00167] The disclosure provides the use of pharmaceutically-acceptable salts of any therapeutic compound described herein. Pharmaceutically-acceptable salts include, for example, acid- addition salts and base-addition salts. The acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically- acceptable salt is an ammonium salt.
[00168] Metal salts can arise from the addition of an inorganic base to a compound of the disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
[00169] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
[00170] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, A-methylpiperidine, A-ethyl pi peri dine. dibenzylamine, piperazine, pyridine, pyrazole, imidazole, or pyrazine.
[00171] In some embodiments, an ammonium salt is a triethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an Af-m ethyl m orphol i ne salt, a piperidine salt, an A-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
[00172] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
[00173] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a trifluoroacetate salt, a mandelate salt, a cinnamate salt, an aspartate salt, a stearate salt, a palmitate salt, a glycolate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt. [00174] Any compound herein can be purified. A compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. [00175] In some embodiments, the compounds of the disclosure show non-lethal toxicity.
Therapeutic Methods.
[00176] Compounds, compositions, and methods of the disclosure can be used to treat a condition in a subject in need thereof, for example, a repeat expansion disorder, such as trinucleotide repeat expansion disorder. The methods can comprise administering to a subject in need thereof a therapeutically-effective amount of a compound disclosed herein.
[00177] A condition to be treated can be a repeat expansion disorder, such as a trinucleotide repeat expansion disorder. The repeat can be present, for example, in a 5' UTR, an intron, an exon, or a 3r UTR of a gene. A trinucleotide repeat expansion disorder can be a disorder that involves an expansion of a CAG repeat (a polyglutamine disease). Non-limiting examples of disorders that comprise an expansion of a CAG repeat include HD (Huntington's disease), with a repeat expansion in the HTT gene, DRPLA (Dentatorubropallidoluysian atrophy), with a repeat expansion in the ATN1 gene, SBMA (Spinal and bulbar muscular atrophy), with a repeat expansion in the AR gene, SCA1 (Spinocerebellar ataxia Type 1), with a repeat expansion in the ATXN1 gene, SCA2 (Spinocerebellar ataxia Type 2), with a repeat expansion in the ATXN2 gene, SCA3 (Spinocerebellar ataxia Type 3), with a repeat expansion in the ATXN3 gene, SCA6 (Spinocerebellar ataxia Type 6), with a repeat expansion in the CACNA1 A gene, SCA7 (Spinocerebellar ataxia Type 7), with a repeat expansion in the ATXN7 gene, SCA12 (Spinocerebellar ataxia Type 12), with a repeat expansion in the PPP2R2B gene, and SCA17 (Spinocerebellar ataxia Type 17), with a repeat expansion in the TBP gene. In some embodiments, a pharmaceutical composition, compound, or method of the disclosure is used for treating an animal model of Huntington’s disease (HD), such as an zQ175KI mouse model of HD. In some embodiments, a composition, compound, or method of the disclosure is used for treating HD. In some embodiments, a composition, compound, or method of the disclosure is used for treating spinocerebellar ataxia type 1. In some embodiments, a composition, compound, or method of the disclosure is used for treating SBMA (Spinal and bulbar muscular atrophy). In some embodiments, a composition, compound, or method of the disclosure is used for treating DRPLA (Dentatorubropallidoluysian atrophy).
[00178] In some embodiments, a composition, compound, or method of the disclosure is used for treating a polyglutamine (PolyQ) disease. In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA1 (Spinocerebellar ataxia Type 1). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA2 (Spinocerebellar ataxia Type 2). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA3 (Spinocerebellar ataxia Type 3). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA6 (Spinocerebellar ataxia Type 6). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA7 (Spinocerebellar ataxia Type 7). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA12 (Spinocerebellar ataxia Type 12). In some embodiments, a composition, compound, or method of the disclosure is used for treating SCA17 (Spinocerebellar ataxia Type 17).
[00179] In some embodiments, a condition to be treated is a neurological condition. In some embodiments, the condition is a neurodegenerative condition. In some embodiments, a condition to be treated is a neuromuscular condition. In some embodiments, the condition is a central nervous system condition and/or a peripheral nervous system condition. In some embodiments, the condition is a multisystem degenerative disorder. In some embodiments, a condition to be treated is a muscular dystrophy. In some embodiments, the condition is associated with aging. In some embodiments, the condition comprises or is associated with cognitive impairment or intellectual disability. In some embodiments, the condition comprises or is associated with depression. In some embodiments, the condition comprises or is associated with tremor. In some embodiments, the condition comprises or is associated with deterioration of motor skills.
In some embodiments, the condition comprises or is associated with impaired glucose tolerance. In some embodiments, the condition comprises or is associated with weight loss. In some embodiments, the condition comprises or is associated with progressive muscle wasting and/or weakness. In some embodiments, the condition comprises or is associated with cataract development. In some embodiments, the condition comprises or is associated with reduced lifespan. In some embodiments, the condition comprises or is associated with myotonia (sustained muscle contraction, e.g., an inability to relax muscles at will). In some embodiments, the condition comprises or is associated with cardiac pathology, such as cardiac conduction abnormalities. In some embodiments, the condition comprises or is associated with arrhythmia. In some embodiments, the condition is a congenital condition. In some embodiments, the condition comprises or is associated with hypotonia. In some embodiments, the condition comprises or is associated with severe generalized weakness. In some embodiments, the condition comprises or is associated with respiratory insufficiency. In some embodiments, the condition comprises or is associated with chorea. In some embodiments, the condition comprises or is associated with a hyperkinetic movement disorder. In some embodiments, the condition comprises or is associated with dementia.
[00180] In some embodiments, the condition is a genetic disorder. In some embodiments, the condition is an autosomal dominant genetic disorder. In some embodiments, the condition comprises or is associated with mis-splicing of gene transcripts. In some embodiments, the condition comprises or is associated with altered protein products that are dysfunctional as a result of mis-splicing. In some embodiments, the condition comprises or is associated with sequestration of splice regulators. In some embodiments, the condition comprises or is associated with aggregation of mRNA in the nucleus. In some embodiments, the severity of the condition is associated with the number of trinucleotide repeats in a trinucleotide repeat expansion. In some embodiments, the condition is a monogenic disorder, e.g., comprises or is associated with an inherited defect in a single gene.
[00181] In some embodiments, the condition is Huntington’s disease. In some embodiments, the condition is juvenile Huntington’s disease. In some embodiments, the condition is adult-onset Huntington’s disease.
[00182] In some embodiments, the disclosure provides a method of treating Huntington’s disease, the method comprising contacting a cell of a subject (e.g., patient) suffering from Huntington’s disease with a compound disclosed herein. Upon contacting a compound disclosed herein with the cell, the compound can penetrate the cell membrane, endosome, and nucleus, engage mutant HTT (mHTT) mRNA, and knock down mHTT expression. In some embodiments, the disclosure provides a method of treating an animal model of HD, the method comprising contacting a cell of a subject (e.g., zQ175KI heterozygous mouse) with a compound disclosed herein. Upon contacting a compound disclosed herein with the cell, the compound can penetrate the cell membrane, endosome, and nucleus, engage mHTT mRNA, and knock down mHTT expression.
[00183] A compound or composition of the disclosure can be administered on the basis of the number of CAG repeats in a gene, for example, in the ATN1 gene, HTT gene, AR gene,
ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1A gene, ATXN7 gene, PPP2R2B gene, or TBP gene. In some embodiments, the efficacy of a compound, composition, or method of the disclosure can vary based on the number of CAG repeats in a gene, for example, in the ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene. The number of CAG repeats in a gene can be variable in the general population, for example, the number of CAG repeats in HD can be in a range of about 6 to about 35 repeats in subjects that do not have HD. The number of CAG repeats in subjects with HD can be at least 36 and in some cases upwards of 100. In some embodiments, the efficacy of a compound, composition, or method of the disclosure can vary based on the number of repeats in the gene or locus.
[00184] In some embodiments, a compound or composition is administered to a subject or contacted to a cell having a gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene) that comprises at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, or at least about 120 CAG repeats. In some embodiments, the gene is HD. In some embodiments, the gene is not HD. In some embodiments, the gene is Atrophin 1 (ATN1). In some embodiments, the gene is not ATN1. In some embodiments, the gene is Huntingtin (HTT). In some embodiments, the gene is not HTT. In some embodiments, the gene is Androgen receptor (AR). In some embodiments, the gene is not AR. In some embodiments, the gene is Ataxin 1 (ATXN1). In some embodiments, the gene not ATXN1. In some embodiments, the gene is Ataxin 2 (ATXN2). In some embodiments, the gene not ATXN2. In some embodiments, the gene is Ataxin 3 (ATXN3). In some embodiments, the gene not ATXN3. In some embodiments, the gene is Ataxin 7 (ATXN7). In some embodiments, the gene not ATXN7. In some embodiments, the gene is CACNA1A. In some embodiments, the gene is not CACNA1A. In some embodiments, the gene is PPP2R2B. In some embodiments, the gene is not PPP2R2B. In some embodiments, the gene is TATA-binding protein (TBP). In some embodiments, the gene is not TBP. In some embodiments the gene is HTT that has at most about 30, at most about 35, at most about 40, at most about 50, at most about 60, at most about 80, or at most about 100 trinucleotide repeats.
[00185] In some embodiments, a trinucleotide repeat expansion comprises at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about
160, at least about 170, at least about 180, at least about 190, at least about 200, at least about
250, at least about 300, at least about 350, at least about 400, at least about 450, at least about
500, at least about 600, at least about 700, at least about 800, at least about 900, at least about
1000, at least about 1500, at least about 2000, at least about 2500, or at least about 3000 trinucleotide repeats, for example, CAG repeats. In some embodiments the trinucleotide repeat expansion has at most about 40, at most about 50, at most about 60, at most about 70, at most about 80, at most about 90, or at most about 100 trinucleotide repeats.
[00186] In some embodiments, a cell, population of cells, or subject that does not have a trinucleotide repeat expansion contains at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 36, at most 37, at most 38, at most 39, at most 40, at most 41, at most 42, at most 43, at most 44, at most 45, at most 50, at most 60, at most 70, at most 80, at most 90, at most 100, at most 110, at most 120, at most 130, at most 140, at most 150, at most 200, or at most 250 copies of the trinucleotide (e.g., CAG) in the repeat region of the gene (e g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1A gene, ATXN7 gene, PPP2R2B gene, or TBP gene).
[00187] In some embodiments, the disclosure provides a method of treating a nucleotide repeat expansion disorder in a subject, comprising administering a compound disclosed herein to the subject. In some embodiments, the nucleotide repeat expansion disorder comprises expression of CAG-repeat-containing mRNA by the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments, the subject is a mouse. [00188] In some embodiments, a compound or composition is administered to a subject or contacted to a cell having a gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene) that comprises at least about 30, least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, at least about 200, at least about 250, at least about 300, at least about 350, at least about 400, at least about 450, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 1500, at least about 2000, at least about 2500, or at least about 3000 repeats, for example, CTG repeats or CUG repeats. In some embodiments the gene has at most about 100, at most about 250, at most about 500, at most about 1000, at most about 2000, at most about 3000, or at most about 5000 repeats.
[00189] In some embodiments, a repeat expansion comprises at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about
170, at least about 180, at least about 190, at least about 200, at least about 250, at least about
300, at least about 350, at least about 400, at least about 450, at least about 500, at least about
600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about
1500, at least about 2000, at least about 2500, or at least about 3000 repeats, for example, CAG repeats. In some embodiments the repeat expansion has at most about 100, at most about 250, at most about 500, at most about 1000, at most about 2000, at most about 3000, or at most about 5000 repeats.
[00190] In some embodiments, a cell, population of cells, or subject that does not have a repeat expansion contains at most 5, at most 10, at most 15, at most 20, at most 25, at most 30, at most 35, at most 36, at most 37, at most 38, at most 39, at most 40, at most 45, at most 50, at most 60, at most 70, at most 80, at most 90, or at most 100 copies of the repeat (e.g., CTG, CUG) in the repeat region of the gene (e.g., ATN1 gene, HTT gene, AR gene, ATXN1 gene, ATXN2 gene, ATXN3 gene, CACNA1 A gene, ATXN7 gene, PPP2R2B gene, or TBP gene).
[00191] In some embodiments, the disclosure provides a method of treating a nucleotide repeat expansion disorder in a subject, comprising administering a compound disclosed herein to the subject. In some embodiments, the repeat expansion disorder comprises expression of repeat- containing mRNA by the subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments, the subject is a mouse.
[00192] In some embodiments, administration of a compound provided herein does not exhibit or substantially does not exhibit immunogenicity. In some embodiments, administration of a compound provided herein does not promote or substantially does not promote generation of neutralizing antibodies, complement factors, pro-inflammatory cytokines, or type 1 interferons upon or after administration of the compound to a subject. In some embodiments, a compound does not activate or substantially does not activate the TLR9 receptor and is not presented or is minimally presented by MHCI or MHCII complexes to the immune system.
[00193] Compounds provided herein can be locally or systemically administered to a subject in need thereof as a therapeutically-effective amount of a compound that binds to a repeat codon. The subject can comprise a bloodstream, a brain, and a blood-brain-barrier. The compound that binds to the repeat codon can enter the brain by passing from the bloodstream through the blood- brain-barrier into the brain.
Modes of Administration.
[00194] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered to a subject in various forms and by various suitable routes of administration.
[00195] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in a systemic manner. [00196] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered parenterally. Parenteral administration can be, for example, by bolus injection or by gradual infusion or perfusion over time. Administration can also be by surgical deposition of a bolus or positioning of a medical device.
[00197] In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered orally. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e g , a pharmaceutical composition) is administered by an intravenous, intratumoral, subcutaneous, intramuscular, intracerebral, intracerebroventricular, intra-articular, intraperitoneal, intracranial, intrathecal, intranasal, buccal, sublingual, oral, or rectal administration route. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intravenous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by subcutaneous administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intracerebroventricular administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by oral administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intrathecal administration.
[00198] Any aforementioned route of administration can be combined with another route of administration. For example, a compound provided herein can be delivered by a first route of administration, and one or more subsequent maintenance doses of the compound can be delivered by the same or a different route of administration. In some embodiments, a compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) is administered by intramuscular administration, and one or more subsequent maintenance doses of the compound or the composition comprising the compound are delivered by subcutaneous administration or intravenous administration.
[00199] Non-limiting examples of suitable modes and routes of administration include oral, topical, parenteral, intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrastemal injection, ophthalmic administration, endothelial administration, local administration, intranasal administration, intrapulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, transdermal administration (e.g., via emulsion/liposome-mediated methods of delivery with the compound optionally packaged into liposomes), epidural administration, absorption through epithelial or mucocutaneous linings (e g., oral mucosa, rectal and intestinal mucosa), intracapsular administration, subcapsular administration, intracardiac administration, transtracheal administration, subcuticular administration, subarachnoid administration, subcapsular administration, intraspinal administration, and intrastemal administration.
[00200] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered via a non-invasive method. Examples of non-invasive modes of administering can include using a needleless injection device, and topical administration, e.g., eye drops. Multiple administration routes can be employed for efficient delivery.
[00201] Depending on the intended mode of administration, the compositions can be in the form of solid, semi solid or liquid dosage forms, such as, e.g., tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, e.g., in unit dosage form suitable for single administration of a precise dosage. The composition can be formulated into any suitable dosage form for administration, e.g., aqueous dispersions, liquids, gels, syrups, elixirs, slurries, and suspensions, for administration to a subject or a patient.
[00202] Solid compositions include, e.g., powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, e.g., solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, e.g., gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [00203] In some embodiments, the composition is formulated into solutions (e.g., for IV administration). In some cases, the pharmaceutical composition is formulated as an infusion. In some cases, the pharmaceutical composition is formulated as an injection.
[00204] A compound provided herein or a composition comprising a compound provided herein (e.g., a pharmaceutical composition) can be administered in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release.
[00205] A composition comprising a compound provided herein can be, e.g., an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements, or has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix -based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
[00206] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, e.g., for about 4, about 8, about 12, about 16, or about 24 hours. A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, e.g., the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.
[00207] A pharmaceutical composition disclosed herein can be targeted to any suitable tissue or cell type. Modes, routes, and compositions provided herein can be suitable to target a compound provided herein to a particular tissue, or a subset of tissues. Non-limiting examples of tissues that can be targeted include kidney (e.g., kidney cortex), joints, cartilage, liver, salivary glands, bone (e.g., bone surface), skin, lung, muscle, pancreas, hair follicles, large intestine mucosa, aortic wall, small intestine mucosa, adrenal gland, stomach mucosa, spleen, bone marrow, lymph nodes, thymus, brain, cerebellum, olfactory bulb, thalamus, caudate putamen, cerebral cortex, substantia nigra, lateral ventricle, choroid plexus, and combinations thereof.
[00208] Compounds can be introduced into cells by, e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles, and viral and non-viral vectors. Compounds provided herein can also be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine-mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-0 permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non-endocytic methods of delivery.
[00209] The method of delivery can depend at least on the cells to be treated and the location of the cells. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor mediated uptake, or viral vectors.
[00210] In some embodiments, a compound disclosed herein is delivered via an implantable device, e.g., synthetic implant design.
[00211] Compounds provided herein can be administered in any physiologically and/or pharmaceutically acceptable vehicle or carrier. Non-limiting examples of pharmaceutically acceptable carriers include saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil/water emulsions or triglyceride emulsions, tablets, and capsules. The choice of suitable physiologically acceptable carrier can vary depending upon the chosen mode of administration. A pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
[00212] Further provided are prodrugs of a compound provided herein. Prodrugs can be covalently bonded carriers that release a compound in vivo when administered to a subject. Prodrugs can be prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, to yield the biologically active compound. Non-limiting examples of prodrugs include acetate, formate, and benzoate derivatives of alcohol and amine functional groups of compounds provided herein. Further, in the case of a carboxylic acid functional group ( — COOH), esters can be used, such as methyl esters and ethyl esters. [00213] In some embodiments, liposomes can be used to facilitate uptake of a compound provided herein into cells. Hydrogels can also be used as vehicles for compound administration. Alternatively, a compound provided herein can be administered in microspheres or microparticles. Alternatively, the use of gas-filled microbubbles complexed with a compound provided herein can enhance delivery to target tissues. Sustained release compositions can also be used, including, e.g., semipermeable polymeric matrices in the form of shaped articles such as films or microcapsules.
[00214] In some embodiments, a compound provided herein is administered to a mammalian subject, e.g., human or domestic animal that is exhibiting the symptoms of a polynucleotide repeat expansion disorder. Compounds provided herein can selectively reduce expression of a mutant protein in the subject. In some embodiments, the subject is a human subject, e.g., a patient diagnosed as having a polynucleotide repeat disease. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered orally. In some embodiments, a compound provided herein is contained in a pharmaceutically acceptable carrier and is delivered intravenously. [00215] In some embodiments, the subject is a vertebrate. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a subject is a non-human subject. In some embodiments, a subject is a veterinary subject.
[00216] In some embodiments, the patient is a vertebrate. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the patient is a primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, guinea pig, C57BL6J mouse, Beagle dog, Gottingen minipig, or Cynomolgus monkey. In some embodiments, a patient is a non-human patient. In some embodiments, a patient is a veterinary patient.
[00217] In some embodiments, a patient and a subject are the same species. In some embodiments, a subject and a patient are human.
[00218] In some embodiments, a patient and a subject are different species. In some embodiments, a subject is human and a patient is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig. In some embodiments, a patient is human and a subject is a non-human, for example, a non-human vertebrate, non-human mammal, non-human primate, ape, monkey, sheep, equine, bovine, porcine, minipig, canine, feline, goat, camelid, rodent, rabbit, mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
[00219] An effective in vivo treatment regimen using the compounds provided herein can vary according to the duration, dose, frequency, and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy can require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome.
[00220] The efficacy of an in vivo administered compound provided herein can be determined from biological samples (e.g., tissue, blood, urine) taken from a subject prior to, during, and subsequent to administration of the compound. Assays of such samples can include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, e.g., by an electrophoretic gel mobility assay; and (2) monitoring the amount of a mutant mRNA or protein in relation to a reference wild-type mRNA or protein as determined by standard techniques such as RT-PCR, Northern blotting, EL1SA, or Western blotting.
[00221] In some embodiments, the compound provided herein is actively taken up by mammalian cells. In further embodiments, the compound provided herein can be conjugated to a transport moiety (e.g., transport peptide) as described herein to facilitate such uptake.
[00222] Compounds provided herein can be administered to subjects to treat (prophylactically or therapeutically) disorders associated with aberrant expression of a mRNA or protein produced from a mutant polynucleotide repeat containing allele. In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual’s genotype and the individual’s response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and/or therapeutic regimen of treatment with the therapeutic agent.
Dosing
[00223] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The dosage (e.g., therapeutically-effective amount) for a compound described herein can be in any amount necessary.
[00224] A compound described herein can be present in a composition or a unit dose in a range of from about 1 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 25 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.
[00225] A compound described herein can be present in a composition or a unit dose in a range of from about 1 μg to about 2000 μg; from about 5 μg to about 1000 μg, from about 10 μg to about 25 μg, from about 50 μg to about 250 μg, from about 100 μg to about 200 μg, from about 1 mg to about 50 μg. from about 50 mg to about 100 mg, from about 100 mg to about 150 μg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 μg, from about 300 μg to about 350 μg, from about 350 μg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 μg, from about 500 μg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 μg, from about 700 μg to about 750 mg, from about 750 mg to about 800 mg, from about 800 μg to about 850 mg, from about 850 mg to about 900 μg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.
[00226] A compound described herein can be present in a composition or a unit dose in an amount of about 0.001 mg, about 0.002 mg, about 0.003 mg, about 0.004 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.
[00227] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at least about 0.001 mg, at least about 0.002 mg, at least about 0.003 mg, at least about 0.004 mg, at least about 0.005 mg, at least about 0.006 mg, at least about 0.007 mg, at least about 0.008 mg, at least about 0.009 mg, at least about 0.01 mg, at least about 0.02 mg, at least about 0.03 mg, at least about 0.04 mg, at least about 0.05 mg, at least about 0.06 mg, at least about 0.07 mg, at least about 0.08 mg, at least about 0.09 mg, at least about 0.1 mg, at least about 0.2 mg, at least about 0.3 mg, at least about 0.4 mg, at least about 0.5 mg, at least about 0.6 mg, at least about 0.7 mg, at least about 0.8 mg, at least about 0.9 mg, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 125 mg, at least about 150 mg, at least about 175 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, at least about 1800 mg, at least about 1850 mg, at least about 1900 mg, at least about 1950 mg, or at least about 2000 mg.
[00228] In some embodiments, a composition is present in a composition or a unit dose in an amount that is at most about 0.001 mg, at most about 0.002 mg, at most about 0.003 mg, at most about 0.004 mg, at most about 0.005 mg, at most about 0.006 mg, at most about 0.007 mg, at most about 0.008 mg, at most about 0.009 mg, at most about 0.01 mg, at most about 0.02 mg, at most about 0.03 mg, at most about 0.04 mg, at most about 0.05 mg, at most about 0.06 mg, at most about 0.07 mg, at most about 0.08 mg, at most about 0.09 mg, at most about 0.1 mg, at most about 0.2 mg, at most about 0.3 mg, at most about 0.4 mg, at most about 0.5 mg, at most about 0.6 mg, at most about 0.7 mg, at most about 0.8 mg, at most about 0.9 mg, at most about 1 mg, at most about 2 mg, at most about 3 mg, at most about 4 mg, at most about 5 mg, at most about 10 mg, at most about 15 mg, at most about 20 mg, at most about 25 mg, at most about 30 mg, at most about 35 mg, at most about 40 mg, at most about 45 mg, at most about 50 mg, at most about 55 mg, at most about 60 mg, at most about 65 mg, at most about 70 mg, at most about 75 mg, at most about 80 mg, at most about 85 mg, at most about 90 mg, at most about 95 mg, at most about 100 mg, at most about 125 mg, at most about 150 mg, at most about 175 mg, at most about 200 mg, at most about 250 mg, at most about 300 mg, at most about 350 mg, at most about 400 mg, at most about 450 mg, at most about 500 mg, at most about 550 mg, at most about 600 mg, at most about 650 mg, at most about 700 mg, at most about 750 mg, at most about 800 mg, at most about 850 mg, at most about 900 mg, at most about 950 mg, at most about 1000 mg, at most about 1050 mg, at most about 1100 mg, at most about 1150 mg, at most about 1200 mg, at most about 1250 mg, at most about 1300 mg, at most about 1350 mg, at most about 1400 mg, at most about 1450 mg, at most about 1500 mg, at most about 1550 mg, at most about 1600 mg, at most about 1650 mg, at most about 1700 mg, at most about 1750 mg, at most about 1800 mg, at most about 1850 mg, at most about 1900 mg, at most about 1950 mg, or at most about 2000 mg.
[00229] In some embodiments, a dose (e.g., a unit dose) is about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, about 250 mg/kg, about 300 mg/kg, about 350 mg/kg, about 400 mg/kg, about 450 mg/kg, about 500 mg/kg, about 550 mg/kg, about 600 mg/kg, about 650 mg/kg, about 700 mg/kg, about 750 mg/kg, about 800 mg/kg, about 850 mg/kg, about 900 mg/kg, about 950 mg/kg, about 1000 mg/kg, about 1050 mg/kg, about 1100 mg/kg, about 1150 mg/kg, about 1200 mg/kg, about 1250 mg/kg, about 1300 mg/kg, about 1350 mg/kg, about 1400 mg/kg, about 1450 mg/kg, about 1500 mg/kg, about 1550 mg/kg, about 1600 mg/kg, about 1650 mg/kg, about 1700 mg/kg, about 1750 mg/kg, about 1800 mg/kg, about 1850 mg/kg, about 1900 mg/kg, about 1950 mg/kg, or about 2000 mg/kg based on body mass of a subject or a patient.
[00230] In some embodiments, a dose (e.g., a unit dose) is at least about 0.001 mg/kg, at least about 0.002 mg/kg, at least about 0.003 mg/kg, at least about 0.004 mg/kg, at least about 0.005 mg/kg, at least about 0.006 mg/kg, at least about 0.007 mg/kg, at least about 0.008 mg/kg, at least about 0.009 mg/kg, at least about 0.01 mg/kg, at least about 0.02 mg/kg, at least about 0.03 mg/kg, at least about 0.04 mg/kg, at least about 0.05 mg/kg, at least about 0.06 mg/kg, at least about 0.07 mg/kg, at least about 0.08 mg/kg, at least about 0.09 mg/kg, at least about 0.1 mg/kg, at least about 0.2 mg/kg, at least about 0.3 mg/kg, at least about 0.4 mg/kg, at least about 0.5 mg/kg, at least about 0.6 mg/kg, at least about 0.7 mg/kg, at least about 0.8 mg/kg, at least about 0.9 mg/kg, at least about 1 mg/kg, at least about 2 mg/kg, at least about 3 mg/kg, at least about 4 mg/kg, at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least about 65 mg/kg, at least about 70 mg/kg, at least about 75 mg/kg, at least about 80 mg/kg, at least about 85 mg/kg, at least about 90 mg/kg, at least about 95 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, at least about 200 mg/kg, at least about 250 mg/kg, at least about 300 mg/kg, at least about 350 mg/kg, at least about 400 mg/kg, at least about 450 mg/kg, at least about 500 mg/kg, at least about 550 mg/kg, at least about 600 mg/kg, at least about 650 mg/kg, at least about 700 mg/kg, at least about 750 mg/kg, at least about 800 mg/kg, at least about 850 mg/kg, at least about 900 mg/kg, at least about 950 mg/kg, at least about 1000 mg/kg, at least about 1050 mg/kg, at least about 1100 mg/kg, at least about 1150 mg/kg, at least about 1200 mg/kg, at least about 1250 mg/kg, at least about 1300 mg/kg, at least about 1350 mg/kg, at least about 1400 mg/kg, at least about 1450 mg/kg, at least about 1500 mg/kg, at least about 1550 mg/kg, at least about 1600 mg/kg, at least about 1650 mg/kg, at least about 1700 mg/kg, at least about 1750 mg/kg, at least about 1800 mg/kg, at least about 1850 mg/kg, at least about 1900 mg/kg, at least about 1950 mg/kg, or at least about 2000 mg/kg based on body mass of a subject or a patient. [00231] In some embodiments, a dose (e.g., a unit dose) is at most about 0.001 mg/kg, at most about 0.002 mg/kg, at most about 0.003 mg/kg, at most about 0.004 mg/kg, at most about 0.005 mg/kg, at most about 0.006 mg/kg, at most about 0.007 mg/kg, at most about 0.008 mg/kg, at most about 0.009 mg/kg, at most about 0.01 mg/kg, at most about 0.02 mg/kg, at most about 0.03 mg/kg, at most about 0.04 mg/kg, at most about 0.05 mg/kg, at most about 0.06 mg/kg, at most about 0.07 mg/kg, at most about 0.08 mg/kg, at most about 0.09 mg/kg, at most about 0.1 mg/kg, at most about 0.2 mg/kg, at most about 0.3 mg/kg, at most about 0.4 mg/kg, at most about 0.5 mg/kg, at most about 0.6 mg/kg, at most about 0.7 mg/kg, at most about 0.8 mg/kg, at most about 0.9 mg/kg, at most about 1 mg/kg, at most about 2 mg/kg, at most about 3 mg/kg, at most about 4 mg/kg, at most about 5 mg/kg, at most about 10 mg/kg, at most about 15 mg/kg, at most about 20 mg/kg, at most about 25 mg/kg, at most about 30 mg/kg, at most about 35 mg/kg, at most about 40 mg/kg, at most about 45 mg/kg, at most about 50 mg/kg, at most about 55 mg/kg, at most about 60 mg/kg, at most about 65 mg/kg, at most about 70 mg/kg, at most about 75 mg/kg, at most about 80 mg/kg, at most about 85 mg/kg, at most about 90 mg/kg, at most about 95 mg/kg, at most about 100 mg/kg, at most about 125 mg/kg, at most about 150 mg/kg, at most about 175 mg/kg, at most about 200 mg/kg, at most about 250 mg/kg, at most about 300 mg/kg, at most about 350 mg/kg, at most about 400 mg/kg, at most about 450 mg/kg, at most about 500 mg/kg, at most about 550 mg/kg, at most about 600 mg/kg, at most about 650 mg/kg, at most about 700 mg/kg, at most about 750 mg/kg, at most about 800 mg/kg, at most about 850 mg/kg, at most about 900 mg/kg, at most about 950 mg/kg, at most about 1000 mg/kg, at most about 1050 mg/kg, at most about 1100 mg/kg, at most about 1150 mg/kg, at most about 1200 mg/kg, at most about 1250 mg/kg, at most about 1300 mg/kg, at most about 1350 mg/kg, at most about 1400 mg/kg, at most about 1450 mg/kg, at most about 1500 mg/kg, at most about 1550 mg/kg, at most about 1600 mg/kg, at most about 1650 mg/kg, at most about 1700 mg/kg, at most about 1750 mg/kg, at most about 1800 mg/kg, at most about 1850 mg/kg, at most about 1900 mg/kg, at most about 1950 mg/kg, or at most about 2000 mg/kg based on body mass of a subject or a patient.
[00232] In some embodiments, a dose (e.g., a unit dose) is from about 0.1 mg/kg to about 2000 mg/kg, from about 1 mg/kg to about 2000 mg/kg, from about 5 mg/kg to about 1000 mg/kg, from about 10 mg/kg to about 25 mg/kg, from about 50 mg/kg to about 250 mg/kg, from about 100 mg/kg to about 200 mg/kg, from about 1 mg/kg to about 50 mg/kg, from about 50 mg/kg to about 100 mg/kg, from about 100 mg/kg to about 150 mg/kg, from about 150 mg/kg to about 200 mg/kg, from about 200 mg/kg to about 250 mg/kg, from about 250 mg/kg to about 300 mg/kg, from about 300 mg/kg to about 350 mg/kg, from about 350 mg/kg to about 400 mg/kg, from about 400 mg/kg to about 450 mg/kg, from about 450 mg/kg to about 500 mg/kg, from about 500 mg/kg to about 550 mg/kg, from about 550 mg/kg to about 600 mg/kg, from about 600 mg/kg to about 650 mg/kg, from about 650 mg/kg to about 700 mg/kg, from about 700 mg/kg to about 750 mg/kg, from about 750 mg/kg to about 800 mg/kg, from about 800 mg/kg to about 850 mg/kg, from about 850 mg/kg to about 900 mg/kg, from about 900 mg/kg to about 950 mg/kg, from about 950 mg/kg to about 1000 mg/kg, about 1 μg/kg to about 2000 μg/kg; from about 5 μg/kg to about 1000 μg/kg, from about 10 μg/kg to about 25 μg/kg, from about 50 μg/kg to about 250 μg/kg, from about 100 μg/kg to about 200 μg/kg, from about 1 μg/kg to about 50 μg/kg, from about 50 μg/kg to about 100 μg/kg, from about 100 μg/kg to about 150 μg/kg, from about 150 μg/kg to about 200 μg/kg, from about 200 μg/kg to about 250 μg/kg, from about 250 μg/kg to about 300 μg/kg, from about 300 μg/kg to about 350 μg/kg, from about 350 μg/kg to about 400 μg/kg, from about 400 μg/kg to about 450 μg/kg, from about 450 μg/kg to about 500 μg/kg, from about 500 μg/kg to about 550 μg/kg, from about 550 μg/kg to about 600 μg/kg, from about 600 μg/kg to about 650 μg/kg, from about 650 μg/kg to about 700 μg/kg, from about 700 μg/kg to about 750 μg/kg, from about 750 μg/kg to about 800 μg/kg, from about 800 μg/kg to about 850 μg/kg, from about 850 μg/kg to about 900 μg/kg, from about 900 μg/kg to about 950 μg/kg, or from about 950 μg/kg to about 1000 μg/kg based on body mass of a subject or a patient.
[00233] Pharmaceutical compositions and formulations described herein can comprise, for example, a compound provided herein at any suitable concentration. A formulation can comprise a composition provided herein at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 350 mg/mL, about 400 mg/mL, about 450 mg/mL, about 500 mg/mL, about 550 mg/mL, about 600 mg/mL, about 650 mg/mL, about 700 mg/mL, about 750 mg/mL, about 800 mg/mL, about 850 mg/mL, about 900 mg/mL, about 950 mg/mL, about 1000 mg/mL, about 1050 mg/mL, about 1100 mg/mL, about 1150 mg/mL, about 1200 mg/mL, about 1250 mg/mL, about 1300 mg/mL, about 1350 mg/mL, about 1400 mg/mL, about 1450 mg/mL, about 1500 mg/mL, about 1550 mg/mL, about 1600 mg/mL, about 1650 mg/mL, about 1700 mg/mL, about 1750 mg/mL, about 1800 mg/mL, about 1850 mg/mL, about 1900 mg/mL, about 1950 mg/mL, or about 2000 mg/mL.
[00234] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at least about 0.001 mg/mL, at least about 0.002 mg/mL, at least about 0.003 mg/mL, at least about 0.004 mg/mL, at least about 0.005 mg/mL, at least about 0.006 mg/mL, at least about 0.007 mg/mL, at least about 0.008 mg/mL, at least about 0.009 mg/mL, at least about 0.01 mg/mL, at least about 0.02 mg/mL, at least about 0.03 mg/mL, at least about 0.04 mg/mL, at least about 0.05 mg/mL, at least about 0.06 mg/mL, at least about 0.07 mg/mL, at least about 0.08 mg/mL, at least about 0.09 mg/mL, at least about 0.1 mg/mL, at least about 0.2 mg/mL, at least about 0.3 mg/mL, at least about 0.4 mg/mL, at least about 0.5 mg/mL, at least about 0.6 mg/mL, at least about 0.7 mg/mL, at least about 0.8 mg/mL, at least about 0.9 mg/mL, at least about 1 mg/mL, at least about 2 mg/mL, at least about 3 mg/mL, at least about 4 mg/mL, at least about 5 mg/mL, at least about 10 mg/mL, at least about 15 mg/mL, at least about 20 mg/mL, at least about 25 mg/mL, at least about 30 mg/mL, at least about 35 mg/mL, at least about 40 mg/mL, at least about 45 mg/mL, at least about 50 mg/mL, at least about 55 mg/mL, at least about 60 mg/mL, at least about 65 mg/mL, at least about 70 mg/mL, at least about 75 mg/mL, at least about 80 mg/mL, at least about 85 mg/mL, at least about 90 mg/mL, at least about 95 mg/mL, at least about 100 mg/mL, at least about 125 mg/mL, at least about 150 mg/mL, at least about 175 mg/mL, at least about 200 mg/mL, at least about 250 mg/mL, at least about 300 mg/mL, at least about 350 mg/mL, at least about 400 mg/mL, at least about 450 mg/mL, at least about 500 mg/mL, at least about 550 mg/mL, at least about 600 mg/mL, at least about 650 mg/mL, at least about 700 mg/mL, at least about 750 mg/mL, at least about 800 mg/mL, at least about 850 mg/mL, at least about 900 mg/mL, at least about 950 mg/mL, at least about 1000 mg/mL, at least about 1050 mg/mL, at least about 1100 mg/mL, at least about 1150 mg/mL, at least about 1200 mg/mL, at least about 1250 mg/mL, at least about 1300 mg/mL, at least about 1350 mg/mL, at least about 1400 mg/mL, at least about 1450 mg/mL, at least about 1500 mg/mL, at least about 1550 mg/mL, at least about 1600 mg/mL, at least about 1650 mg/mL, at least about 1700 mg/mL, at least about 1750 mg/mL, at least about 1800 mg/mL, at least about 1850 mg/mL, at least about 1900 mg/mL, at least about 1950 mg/mL, or at least about 2000 mg/mL.
[00235] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of at most about 0.002 mg/mL, at most about 0.003 mg/mL, at most about 0.004 mg/mL, at most about 0.005 mg/mL, at most about 0.006 mg/mL, at most about 0.007 mg/mL, at most about 0.008 mg/mL, at most about 0.009 mg/mL, at most about 0.01 mg/mL, at most about 0.02 mg/mL, at most about 0.03 mg/mL, at most about 0.04 mg/mL, at most about 0.05 mg/mL, at most about 0.06 mg/mL, at most about 0.07 mg/mL, at most about 0.08 mg/mL, at most about 0.09 mg/mL, at most about 0.1 mg/mL, at most about 0.2 mg/mL, at most about 0.3 mg/mL, at most about 0.4 mg/mL, at most about 0.5 mg/mL, at most about 0.6 mg/mL, at most about 0.7 mg/mL, at most about 0.8 mg/mL, at most about 0.9 mg/mL, at most about 1 mg/mL, at most about 2 mg/mL, at most about 3 mg/mL, at most about 4 mg/mL, at most about 5 mg/mL, at most about 10 mg/mL, at most about 15 mg/mL, at most about 20 mg/mL, at most about 25 mg/mL, at most about 30 mg/mL, at most about 35 mg/mL, at most about 40 mg/mL, at most about 45 mg/mL, at most about 50 mg/mL, at most about 55 mg/mL, at most about 60 mg/mL, at most about 65 mg/mL, at most about 70 mg/mL, at most about 75 mg/mL, at most about 80 mg/mL, at most about 85 mg/mL, at most about 90 mg/mL, at most about 95 mg/mL, at most about 100 mg/mL, at most about 125 mg/mL, at most about 150 mg/mL, at most about 175 mg/mL, at most about 200 mg/mL, at most about 250 mg/mL, at most about 300 mg/mL, at most about 350 mg/mL, at most about 400 mg/mL, at most about 450 mg/mL, at most about 500 mg/mL, at most about 550 mg/mL, at most about 600 mg/mL, at most about 650 mg/mL, at most about 700 mg/mL, at most about 750 mg/mL, at most about 800 mg/mL, at most about 850 mg/mL, at most about 900 mg/mL, at most about 950 mg/mL, at most about 1000 mg/mL, at most about 1050 mg/mL, at most about 1100 mg/mL, at most about 1150 mg/mL, at most about 1200 mg/mL, at most about 1250 mg/mL, at most about 1300 mg/mL, at most about 1350 mg/mL, at most about 1400 mg/mL, at most about 1450 mg/mL, at most about 1500 mg/mL, at most about 1550 mg/mL, at most about 1600 mg/mL, at most about 1650 mg/mL, at most about 1700 mg/mL, at most about 1750 mg/mL, at most about 1800 mg/mL, at most about 1850 mg/mL, at most about 1900 mg/mL, at most about 1950 mg/mL, or at most about 2000 mg/mL.
[00236] In some embodiments, a formulation provided herein comprises a compound provided herein at a concentration of about 1 mg/mL to about 2000 mg/mL; from about 5 mg/mL to about 1000 mg/mL, from about 10 mg/mL to about 25 mg/mL, from about 50 mg/mL to about 250 mg/mL, from about 100 mg/mL to about 200 mg/mL, from about 1 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 250 mg/mL, from about 250 mg/mL to about 300 mg/mL, from about 300 mg/mL to about 350 mg/mL, from about 350 mg/mL to about 400 mg/mL, from about 400 mg/mL to about 450 mg/mL, from about 450 mg/mL to about 500 mg/mL, from about 500 mg/mL to about 550 mg/mL, from about 550 mg/mL to about 600 mg/mL, from about 600 mg/mL to about 650 mg/mL, from about 650 mg/mL to about 700 mg/mL, from about 700 mg/mL to about 750 mg/mL, from about 750 mg/mL to about 800 mg/mL, from about 800 mg/mL to about 850 mg/mL, from about 850 mg/mL to about 900 mg/mL, from about 900 mg/mL to about 950 mg/mL, from about 950 mg/mL to about 1000 mg/mL, about 1 μg/mL to about 2000 μg/mL; from about 5 μg/mL to about 1000 μg/mL, from about 10 μg/mL to about 25 μg/mL, from about 50 μg/mL to about 250 μg/mL, from about 100 μg/mL to about 200 μg/mL, from about 1 μg/mL to about 50 μg/mL, from about 50 μg/mL to about 100 μg/mL, from about 100 μg/mL to about 150 μg/mL, from about 150 μg/mL to about 200 μg/mL, from about 200 μg/mL to about 250 μg/mL, from about 250 μg/mL to about 300 μg/mL, from about 300 μg/mL to about 350 μg/mL, from about 350 μg/mL to about 400 μg/mL, from about 400 μg/mL to about 450 μg/mL, from about 450 μg/mL to about 500 μg/mL, from about 500 μg/mL to about 550 μg/mL, from about 550 μg/mL to about 600 μg/mL, from about 600 μg/mL to about 650 μg/mL, from about 650 μg/mL to about 700 μg/mL, from about 700 μg/mL to about 750 μg/mL, from about 750 μg/mL to about 800 μg/mL, from about 800 μg/mL to about 850 μg/mL, from about 850 μg/mL to about 900 μg/mL, from about 900 μg/mL to about 950 μg/mL, or from about 950 μg/mL to about 1000 μg/mL.
[00237] In some embodiments, a formulation of the disclosure delivers about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 0.1 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 0.2 mg/kg AED of a compound of the disclosure. In some embodiments, a formulation of the disclosure delivers about 0.3 mg/kg AED of a compound of the disclosure.
[00238] An approximate dose can be predicted or determined on the basis of data existing in other species. In some embodiments, allometric scaling can be used to exchange a drug dose based on normalization of dose to body surface area. Allometric scaling considers the sizes of individual species based on body surface area, which is related to metabolic rate of an animal that is established through evolutionary adaptation of animals to their size. A no observed adverse effect level (NOAEL) is first determined in an animal species, the NOAEL is converted to a human equivalent dose (HED), an appropriate animal species is selected, a safety factor is applied, and a pharmacologically active dose is determined.
[00239] NOAEL, the highest dose level that does not cause significant adverse effects, is a typical index for safety obtained from animal experiments to determine a safe starting dose. NOAEL values can be converted to HED on the basis of the body surface correction factor using appropriate scaling factors from animal species. TABLE 5 lists HED calculation guidelines based on body surface areas. HED is determined using the equation:
HED (mg/kg) = Animal NOAEL (mg/kg) x (Weightanimai[kg]/Weighthuman[kg])(1'067) [00240] The HED is divided by a factor value of 10 to increase safety of the first human dose. The safety factor is accountable for differences in physiological and biological processes between human and animal species.
[00241] The correction factor (Km) is estimated by dividing the average body weight (kg) of a species to its body surface area (m2). The Km factor values of various animal species of TABLE 5 is used to estimate the HED as:
HED (mg/kg) = Animal doses (mg/kg) x (Animal Km/Hurnan Km); or HED (mg/kg) = Animal doses (mg/kg) x Km ratio [00242] However, conversion between species based on mg/m2 is not supported for drugs administered by topical, nasal, subcutaneous, or intramuscular routes, as well as proteins administered parenterally with molecular weight >100,000 Daltons.
TABLE 5
Figure imgf000096_0001
Figure imgf000097_0001
[00243] TABLE 6 provides animal equivalent dose (AED) calculation guidelines based on body surface area. The animal equivalent dose (AED) can also be calculated on the basis of body surface area by either dividing or multiplying the human dose (mg/kg) by the Km ratio provided in TABLE 6. AED can be calculated using the equation:
AED (mg/kg) = Human doses (mg/kg) x Km ratio
TABLE 6
Figure imgf000097_0002
Figure imgf000098_0001
[00244] For parenteral administration, HED conversion (mg/kg) is also based on body surface area normalization. The conversion can be made by dividing the NOAEL in appropriate species by the conversion factor. TABLE 7 provides guidelines for maximum injection volume, by species, site location, and gauge size. Injection volume of parenteral formulation is calculated by the following equation:
Injection volume (mL) = [Animal weight (kg) x Animal doses (mg/kg)] / Concentration (mg/kg)
TABLE 7
Figure imgf000099_0001
Figure imgf000100_0001
Therapeutic Effects.
[00245] Compounds disclosed herein can be effective for reducing an expression level of a disease-causing Huntingtin gene in a subject. Various analytical techniques can be used to determine or quantify gene expression level, mRNA expression level, or protein expression level in the subject, e g., in a tissues and/or other samples collected from study patients (e.g., blood, plasma, urine, feces, etc). Non-limiting examples of techniques to determine gene expression level include sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), immunoassaying, immunoblotting, western blotting, fluorescent western blotting, enzyme-linked immunosorbent assay (EL1SA), and AlphaL1SA® assaying.
[00246] In some embodiments, if, in a seven day study: a) in a first control group, six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 10% lesser than is a mean expression of the non- disease-causing Huntingtin gene in the first control group; ii) a mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 20% lesser than is a mean expression of the disease- causing Huntingtin gene in the second control group; and iii) the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is the mean expression of the non- disease-causing Huntingtin gene in the first test group.
[00247] In some embodiments, the nucleic acid molecule associated with Huntington’s disease is a mRNA sequence transcribed from the disease-causing Huntingtin gene. In some embodiments, the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 10% lesser than to about 20% lesser than a mean expression of the non-disease-causing Huntingtin gene in the first control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 20% lesser than to about 40% lesser than a mean expression of the disease-causing Huntingtin gene in the second control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 20% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
[00248] In some embodiments, the present disclosure provides a method of treating Huntington’s disease, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
[00249] In some embodiments, if, in a seven day study: a) in a first control group, six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 60 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 10% lesser than is a mean expression of the non- disease-causing Huntingtin gene in the first control group; ii) a mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 20% lesser than is a mean expression of the disease- causing Huntingtin gene in the second control group; and iii) the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is the mean expression of the non- disease-causing Huntingtin gene in the first test group.
[00250] In some embodiments, the nucleic acid molecule associated with Huntington’s disease is a mRNA sequence transcribed from the disease-causing Huntingtin gene. In some embodiments, the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 10% lesser than to about 20% lesser than a mean expression of the non-disease-causing Huntingtin gene in the first control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 20% lesser than to about 40% lesser than a mean expression of the disease-causing Huntingtin gene in the second control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 20% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
[00251] In some embodiments, the present disclosure provides a compound comprising a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
[00252] In some embodiments, if, in a seven day study: a) in a first control group, six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 5% greater than is a mean expression of the non-disease-causing Huntingtin gene in the first control group; ii) a mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is a mean expression of the disease-causing Huntingtin gene in the second control group; and iii) the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is the mean expression of the non-disease-causing Huntingtin gene in the first test group.
[00253] In some embodiments, the nucleic acid molecule associated with Huntington’s disease is a DNA sequence of the disease-causing Huntingtin gene. In some embodiments, the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 5% greater than to about 15% greater than the mean expression of the non-disease- causing Huntingtin gene in the first control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 25% lesser than the mean expression of the disease-causing Huntingtin gene in the second control group. In some embodiments, the mean expression of the disease- causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 30% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
[00254] In some embodiments, the present disclosure provides a method of treating Huntington’s disease, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound, wherein the compound comprises a peptide nucleic acid sequence, wherein the peptide nucleic acid sequence binds to a nucleic acid molecule associated with Huntington’s disease.
[00255] In some embodiments, if, in a seven day study: a) in a first control group, six mice who possess a non-disease-causing Huntingtin gene are subcutaneously administered a vehicle on days 1 and 4; b) in a second control group, six mice who possess a disease-causing Huntingtin gene, wherein the disease-causing Huntingtin gene possesses 190 CAG repeats in exon 1, are subcutaneously administered the vehicle on days 1 and 4; c) in a first test group, six mice who possess the non-disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4; and d) in a second test group, six mice who possess the disease-causing Huntingtin gene are administered 30 mg/kg of the compound in the vehicle on days 1 and 4, then, i) a mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be at least 5% greater than is a mean expression of the nondisease-causing Huntingtin gene in the first control group; ii) a mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is a mean expression of the disease- causing Huntingtin gene in the second control group; and iii) the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be at least 10% lesser than is the mean expression of the nondisease-causing Huntingtin gene in the first test group.
[00256] In some embodiments, the nucleic acid molecule associated with Huntington’s disease is a DNA sequence of the disease-causing Huntingtin gene. In some embodiments, the mean expression of the non-disease-causing Huntingtin gene in the first test group is determined to be from about 5% greater than to about 15% greater than the mean expression of the non-disease- causing Huntingtin gene in the first control group. In some embodiments, the mean expression of the disease-causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 25% lesser than the mean expression of the disease-causing Huntingtin gene in the second control group. In some embodiments, the mean expression of the disease- causing Huntingtin gene in the second test group is determined to be from about 10% lesser than to about 30% lesser than the mean expression of the non-disease-causing Huntingtin gene in the first test group.
[00257] In some embodiments, the compounds of the disclosure show non-lethal toxicity.
Pharmaceutical compositions
[00258] A pharmaceutical composition of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
[00259] Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals. In some embodiments, a subject is a patient.
[00260] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
[00261] A pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release. [00262] For oral administration, pharmaceutical compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject. Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hy droxy ethyl- 1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremophor, DMSO, and potassium phosphate buffer.
[00263] Pharmaceutical preparations can be formulated for intravenous administration. The phannaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00264] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00265] The compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject. The compounds of the disclosure can be applied to an accessible body cavity.
[00266] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
[00267] In practicing the methods of treatment or use provided herein, therapeutically-effective amounts of the compounds described herein can be administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
[00268] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
[00269] The pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically- acceptable salt form. Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[00270] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [00271] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
[00272] Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
[00273] A composition of the disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
[00274] In some, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
[00275] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
[00276] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
[00277] Multiple therapeutic agents can be administered in any order or simultaneously. In some embodiments, a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills. The agents can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month. [00278] Therapeutic agents described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary. For example, the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition. The compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein. [00279] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.
[00280] Pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged injectables, vials, or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative. Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi dose containers with a preservative.
[00281] Pharmaceutical compositions provided herein, can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins. The other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
[00282] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
[00283] For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
[00284] Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations. [00285] Compounds can be delivered via liposomal technology. The use of liposomes as drug carriers can increase the therapeutic index of the compounds. Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine). A liposome design can employ surface ligands for attaching to unhealthy tissue. Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV). Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues. Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small sized liposomes are better suited to achieve passive targeting. PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect. Additionally, liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells. Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
[00286] Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof. Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti -adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
Compositions of the disclosure can be packaged as a kit. In some embodiments, a kit includes written instructions on the administration/use of the composition. The written material can be, for example, a label. The written material can suggest conditions methods of administration. The instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy. The written material can be a label. In some embodiments, the label can be approved by a regulatory agency, for example the U S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
EMBODIMENTS
[00287] The following non-limiting embodiments in numbered paragraph form provide illustrative examples of the invention, but do not limit the scope of the invention.
[00288] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guani dinoalkyl; ii) C(0)-alkyl; and iii) guani di noalkyl.
[00289] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
[00290] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG)Z (SEQ ID NO: 135) or (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1-100, wherein the structure is attached to a chain of atoms bearing a series of side chains, wherein the series of side chains has a sub-series of three consecutive side chains that are: i) guanidinoalkyl; ii) C(0)-alkyl; and iii) guanidinoalkyl. [00291] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG)Z (SEQ ID NO: 135) or (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1-100 (SEQ ID NO: 135), wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has two consecutive side chains that are each independently guanidinoalkyl.
[00292] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence that contains a subsequence that is (CAG)Z (SEQ ID NO: 135) or (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1-100 (SEQ ID NO: 135), wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
[00293] A compound comprising a structure, wherein the structure binds to a nucleic acid sequence transcribed from a gene associated with a neurodegenerative disease phenotype, wherein the structure is attached to a chain of atoms, wherein carbon atoms of the chain of atoms bear a series of side chains, wherein the series of side chains has six consecutive side chains that each independently bear a positive charge at physiological pH.
[00294] The compound of paragraph [00288] or paragraph [00290], wherein the sub-series of three consecutive side chains is bound to a sub-series of the chain of atoms comprising a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, a sixth atom that is bound to the fifth atom, and a seventh atom that is bound to the sixth atom.
[00295] The compound of any one of paragraphs [00288], [00290], and [00294], wherein each of the fifth atom and the sixth atom is not bound to any of guanidinoalkyl and C(0)-alkyl. [00296] The compound of any one of paragraphs [00288], [00290], and [00294], wherein each of the second atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00297] The compound of any one of paragraphs [00288], [00290], and [00294], wherein each of the first atom, the second atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00298] The compound of any one of paragraphs [00288], [00290], and [00294], wherein each of the first atom, the fourth atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00299] The compound of any one of paragraphs [00288], [00290], and [00294], wherein each of the second atom, the fourth atom, the fifth atom, and the sixth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00300] The compound of any one of paragraphs [00288], [00290], and [00294]-[00297], wherein the fourth atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00301] The compound of any one of paragraphs [00288], [00290], [00294]-[00296], and [00298], wherein the second atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00302] The compound of any one of paragraphs [00288], [00290], [00294]-[00296], and [00299], wherein the first atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains.
[00303] The compound of any one of paragraphs [00288], [00290], [00294]-[00296], [00299], and [00302], Wherein the seventh atom is bound to one guanidinoalkyl of the sub-series of three consecutive side chains. [00304] The compound of any one of paragraphs [00288], [00290], and [00294]-[00303], wherein the third atom is bound the C(0)-alkyl of the sub-series of three consecutive side chains.
[00305] The compound of paragraph [00294] or paragraph [00295], wherein the sub-series of the chain of atoms further comprises a eighth atom that is bound to the seventh atom, a ninth atom that is bound to the eighth atom, a tenth atom that is bound to the ninth atom, an eleventh atom that is bound to the tenth atom, and a twelfth atom that is bound to the eleventh atom. [00306] The compound of paragraph [00305], wherein each of the eleventh atom and the twelfth atom is not bound to any of guani dinoalkyl and C(0)-alkyl.
[00307] The compound of paragraph [00305], wherein each of the eighth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(0)-alkyl.
[00308] The compound of paragraph [00305], wherein each of the seventh atom, the eighth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(O)- alkyl.
[00309] The compound of any one of paragraphs [00305]-[00308], wherein the tenth atom is bound to guanidinoalkyl.
[00310] The compound of paragraph [00305], wherein each of the seventh atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(0)-alkyl. [00311] The compound of any one of paragraphs [00305], [00306], and [00310], wherein the eighth atom is bound to guanidinoalkyl.
[00312] The compound of paragraph [00305], wherein each of the eighth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to any of guanidinoalkyl and C(0)-alkyl. [00313] The compound of any one of paragraphs [00305]-[00312], wherein the ninth atom is bound to C(0)-alkyl.
[00314] The compound of any one of paragraphs [00305]-[00313], wherein the first through twelfth atoms of the sub-series of the chain of atoms together form a repeating unit of a polymer backbone.
[00315] The compound of paragraph [00314], wherein the polymer backbone is a peptide nucleic acid backbone.
[00316] The compound of paragraph [00289] or paragraph [00291], wherein the chain of atoms comprises a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, a sixth atom that is bound to the fifth atom, a seventh atom that is bound to the sixth atom, an eighth atom that is bound to the seventh atom, a ninth atom that is bound to the eighth atom, a tenth atom that is bound to the ninth atom, an eleventh atom that is bound to the tenth atom, and a twelfth atom that is bound to the eleventh atom.
[00317] The compound of paragraph [00316], wherein each of the third atom, the fifth atom, the sixth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00318] The compound of paragraph [00316], wherein each of the second atom, the third atom, the fifth atom, the sixth atom, the eighth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00319] The compound of paragraph [00316], wherein each of the first atom, the second atom, the third atom, the fifth atom, the sixth atom, the seventh atom, the eighth atom, the ninth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00320] The compound of any one of paragraphs [00316]-[00319], wherein the fourth atom is bound to guanidinoalkyl.
[00321] The compound of any one of paragraphs [00316]-[00319], wherein the tenth atom is bound to guanidinoalkyl.
[00322] The compound of paragraph [00316], wherein each of the second atom, the third atom, the fourth atom, the fifth atom, the sixth atom, the eighth atom, the ninth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00323] The compound of any one of paragraphs [00316]-[00318], and [00322], wherein the first atom is bound to guanidinoalkyl.
[00324] The compound of any one of paragraphs [00316]-[00318], [00322], and [00323], wherein the seventh atom is bound to guanidinoalkyl.
[00325] The compound of paragraph [00316], wherein each of the first atom, the third atom, the fourth atom, the fifth atom, the sixth atom, the seventh atom, the ninth atom, the tenth atom, the eleventh atom, and the twelfth atom is not bound to guanidinoalkyl.
[00326] The compound of paragraph [00316] or paragraph [00325], wherein the second atom is bound to guanidinoalkyl.
[00327] The compound of any one of paragraphs [00316], [00325], and [00326], wherein the eighth atom is bound to guanidinoalkyl.
[00328] The compound of any one of paragraphs [00316]-[00327], wherein the third atom is bound to a C(0)-alkyl group.
[00329] The compound of any one of paragraphs [00316]-[00328], wherein the ninth atom is bound to a C(0)-alkyl group.
[00330] The compound of any one of paragraphs [00316]-[00329], wherein the first through twelfth atoms together form a repeating unit of a polymer backbone.
[00331] The compound of paragraph [00330], wherein the polymer backbone is a peptide nucleic acid backbone.
[00332] The compound of paragraph [00292] or paragraph [00293], wherein the chain of atoms comprises a first atom that is bound to a second atom, a third atom that is bound to the second atom, a fourth atom that is bound to the third atom, a fifth atom that is bound to the fourth atom, and a sixth atom that is bound to the fifth atom, wherein the first atom is bound to a side chain of the series of side chains, and each of the second atom, the third atom, the fourth atom, the fifth atom, and the sixth atom is not bound to a side chain of the series of side chains.
[00333] The compound of paragraph [00332], wherein the third atom is bound to a C(0)-alkyl group.
[00334] The compound of paragraph [00332], wherein the second atom is bound to a C(0)-alkyl group.
[00335] The compound of paragraph [00332], wherein the sixth atom is bound to a C(0)-alkyl group.
[00336] The compound of any one of paragraphs [00332]-[00335], wherein the first through sixth atoms together form a repeating unit of a polymer backbone.
[00337] The compound of paragraph [00336], wherein the polymer backbone is a peptide nucleic acid backbone.
[00338] The compound of any one of paragraphs [00292], [00293], and [00332]-[00337], wherein each of the side chains is independently aminoalkyl, guanidinoalkyl, ureidolalkyl, amidinoalkyl, morpholinoalkyl, piperidinylalkyl, piperazinylalkyl, or pyrrolidinylalkyl.
[00339] The compound of any one of paragraphs [00292], [00293], and [00332]-[00337], wherein each of the side chains is independently aminoalkyl or guanidinoalkyl.
[00340] The compound of any one of paragraphs [00292], [00293], and [00332]-[00337], wherein each of the side chains is independently guanidinoalkyl.
[00341] The compound of any one of paragraphs [00288]-[00291], [00294]-[00331], and [00338]-[00340], wherein each guanidinoalkyl is independently H, 3 -guani dinoprop- 1-yl, or 4- guani dinobut- 1 -y 1.
[00342] The compound of any one of paragraphs [00288]-[00291], [00294]-[00331], and [00338]-[00340], wherein each guanidinoalkyl is 3-guanidinoprop-l-yl.
[00343] The compound of any one of paragraphs [00288]-[00291], [00294]-[00331], and [00338]-[00340], wherein each guanidinoalkyl is 4-guanidinobut-l-yl.
[00344] The compound of any one of paragraphs [00288], [00290], [00294]-[00304], [00306], [00308], [00310], [00312], [00313], [00328], [00329], [00333], [00334], and [00335], wherein each C(0)-alkyl group is independently acetyl.
[00345] The compound of any one of paragraphs [00288], [00289], and [00293], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00346] The compound of any one of paragraphs [00288], [00289], [00293], and [00345], wherein the nucleic acid sequence contains a subsequence that is (CAG)Z (SEQ ID NO: 135) or (CTG)z (SEQ ID NO: 182), wherein z is an integer from 1-100.
[00347] The compound of any one of paragraphs [00290], [00291], [00292], and [00346], wherein the structure binds to the nucleic acid sequence at the subsequence that is (CAG)Z (SEQ ID NO: 135).
[00348] The compound of any one of paragraphs [00290], [00291], [00292], and [00346], wherein the structure binds to the nucleic acid sequence at the subsequence that is (CTG)Z (SEQ ID NO: 182).
[00349] The compound of any one of paragraphs [00346]-[00348], wherein the nucleic acid sequence is a mRNA sequence.
[00350] The compound of any one of paragraphs [00288]-[00349], wherein the structure is a oligonucleotide or oligonucleotide analogue.
[00351] The compound of any one of paragraphs [00288]-[00350], wherein the structure is a peptide nucleic acid.
[00352] A compound comprising a structure that is:
N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA †£-
Figure imgf000116_0001
-Terminus wherein:
A-Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
Z is a peptide nucleic acid sequence;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent; L5 is a linker group or absent;
L6 is a linker group or absent; and or a pharmaceutically-acceptable salt or ionized form thereof.
[00353] The compound of paragraph [00352], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO: 1, PNA SEQ NO: 2, PNA SEQ NO: 3, PNA SEQ NO: 4, PNA SEQ NO: 5, PNA SEQ NO: 6, PNA SEQ NO: 7, PNA SEQ NO: 8, PNA SEQ NO: 9, PNA SEQ NO: 10, PNA SEQ NO: 11, PNA SEQ NO: 12, PNA SEQ NO: 13, PNA SEQ NO: 14, PNA SEQ NO: 15, PNA SEQ NO: 16, PNA SEQ NO: 17, PNA SEQ NO: 18, PNA SEQ NO: 19, PNA SEQ NO: 20, PNA SEQ NO: 21, PNA SEQ NO: 22, PNA SEQ NO: 23, PNA SEQ NO: 34,
PNA SEQ NO: 25, PNA SEQ NO: 26, PNA SEQ NO: 27, PNA SEQ NO: 28, PNA SEQ NO:
29, PNA SEQ NO: 30, PNA SEQ NO: 31, PNA SEQ NO: 32, PNA SEQ NO: 33, PNA SEQ NO: 34, PNA SEQ NO: 35, PNA SEQ NO: 36, PNA SEQ NO: 37, or PNA SEQ NO: 38.
[00354] The compound of paragraph [00352], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO: 12, PNA SEQ NO: 14, PNA SEQ NO: 16, PNA SEQ NO: 18, PNA SEQ NO: 20, PNA SEQ NO: 22, PNA SEQ NO: 34, PNA SEQ NO: 35, or PNA SEQ NO: 38. [00355] The compound of paragraph [00352], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO: 39.
[00356] The compound of paragraph [00352], wherein Z is
Figure imgf000117_0001
each R1 is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; the first number of units with variables defined independently is at least 3.
[00357] The compound of paragraph [00356], wherein in each odd unit of the first number of units with variables defined independently, R1 and Ralpha1 are each H.
[00358] The compound of paragraph [00356] or paragraph [00357], wherein for each even unit of the first number of units with variables defined independently, (a) R1 is independently alkyl that is unsubstituted or substituted, and Ralpha1 is H; or (b) R1 is H, and Ralpha1 is independently alkyl that is unsubstituted or substituted.
[00359] The compound of paragraph [00356] or paragraph [00357], wherein for each even unit of the first number of units with variables defined independently, (a) R1 is independently alkyl that is substituted, and Ralpha1 is H; or (b) R1 is H, and Ralpha1 is independently alkyl that is substituted.
[00360] The compound of paragraph [00356], wherein in each even unit of the first number of units with variables defined independently, R1 and Ralpha1 are each H.
[00361] The compound of paragraph [00356] or paragraph [00360], wherein for each odd unit of the first number of units with variables defined independently, (a) R1 is independently alkyl that is unsubstituted or substituted, and Ralpha1 is H; or (b) R1 is H, and Ralpha1 is independently alkyl that is unsubstituted or substituted.
[00362] The compound of paragraph [00356] or paragraph [00360], wherein for each odd unit of the first number of units with variables defined independently, (a) R1 is independently alkyl that is substituted, and Ralpha1 is H; or (b) R1 is H, and Ralpha1 is independently alkyl that is substituted.
[00363] The compound of any one of paragraphs [00352] and [00356]-[00362], wherein Z is a peptide nucleic acid sequence complementary to a nucleic acid sequence selected from the group consisting of: CAG, CAGC, CAGCA, CAGCAG, CAGCAGC, CAGCAGCA, CAGCAGCAG, CAGCAGCAGC (SEQ ID NO: 96), CAGCAGCAGCA (SEQ ID NO: 97),
CAGCAGCAGCAG (SEQ ID NO: 98), CAGCAGCAGCAGC (SEQ ID NO: 99), CAGCAGCAGC AGCA (SEQ ID NO: 100), CAGCAGCAGCAGC AG (SEQ ID NO: 101), CAGCAGCAGC AGCAGC (SEQ ID NO: 102), CAGCAGCAGCAGC AGCA (SEQ ID NO: 103), CAGC AGCAGC AGCAGC AG (SEQ ID NO: 104), CAGCAGCAGCAGCAGCAGC (SEQ ID NO: 105), CAGC AGCAGC AGCAGC AGCA (SEQ ID NO: 106),
CAGCAGC AGCAGC AGCAGC AG (SEQ ID NO: 107), CAGC AGCAGC AGCAGC AGCAGC (SEQ ID NO: 108), CAGCAGCAGCAGCAGCAGC AGCA (SEQ ID NO: 109),
CAGC AGCAGC AGCAGCAGCAGC AG (SEQ ID NO: 110), AGC, AGCA, AGCAG, AGCAGC, AGCAGC A, AGC AGCAG, AGC AGC AGC, AGC AGC AGC A (SEQ ID NO: 151), AGCAGC AGCAG (SEQ ID NO: 152), AGCAGCAGCAGC (SEQ ID NO: 153),
AGC AGC AGC AGCA (SEQ ID NO: 154), AGC AGC AGC AGC AG (SEQ ID NO: 155), AGCAGC AGCAGCAGC (SEQ ID NO: 156), AGC AGCAGCAGCAGC A (SEQ ID NO: 157), AGC AGC AGC AGC AGC AG (SEQ ID NO: 158), AGC AGC AGC AGCAGC AGC (SEQ ID NO: 159), AGCAGCAGC AGCAGCAGC A (SEQ ID NO: 160), AGC AGCAGCAGC AGC AGC AG (SEQ ID NO: 161), AGCAGCAGCAGCAGCAGCAGC (SEQ ID NO: 162),
AGCAGC AGCAGCAGC AGCAGCA (SEQ ID NO: 163),
AGC AGC AGC AGC AGC AGC AGC AG (SEQ ID NO: 164),
AGCAGC AGCAGC AGC AGC AGC AGC (SEQ ID NO: 165), GCA, GCAG, GCAGC, GCAGCA, GCAGCAG, GCAGCAGC, GCAGCAGCA, GCAGCAGCAG (SEQ ID NO: 166), GCAGCAGCAGC (SEQ ID NO: 167), GCAGCAGCAGCA (SEQ ID NO: 168), GCAGCAGCAGCAG (SEQ ID NO: 169), GCAGCAGCAGCAGC (SEQ ID NO: 170), GCAGCAGCAGCAGCA (SEQ ID NO: 171), GCAGCAGCAGCAGC AG (SEQ ID NO: 172), GCAGCAGCAGCAGC AGC (SEQ ID NO: 173), GCAGCAGCAGCAGCAGCA (SEQ ID NO: 174), GCAGCAGCAGCAGCAGCAG (SEQ ID NO: 175), GCAGCAGCAGCAGCAGCAGC (SEQ ID NO: 176), GCAGCAGCAGC AGCAGCAGCA (SEQ ID NO: 177),
GCAGCAGCAGC AGC AGC AGC AG (SEQ ID NO: 178),
GCAGCAGCAGC AGC AGC AGC AGC (SEQ ID NO: 179), and GCAGCAGCAGC AGC AGCAGCAGCA (SEQ ID NO: 180).
[00364] The compound of any one of paragraphs [00356]-[00362], wherein the first number of units with variables defined independently is 11-50.
[00365] The compound of any one of paragraphs [00356]-[00362], wherein the first number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30.
[00366] The compound of paragraph [00352], wherein Z is (Yx)a(Yxx)b(Yx)c(Yxx)d(Y)e(x)f, wherein: each Y is independently
Figure imgf000119_0001
each x is independently
Figure imgf000119_0002
each R1 is independently alkyl that is unsubstituted or substituted and Ralpha1 is H, or each R1 is H and each Ralpha1 is independently alkyl that is unsubstituted or substituted; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; a is 0, 1, 2, or 3; b is 1, 2, or 3; c is 1, 2, or 3; d is 1, 2, 3, or 4; e is 0 or 1, and f is 0 or 1.
[00367] The compound of paragraph [00366], wherein a is 1; b is 2; c is 2; d is 1, 2, 3, or 4; e is 0 or 1; and f is 0 or 1. [00368] The compound of paragraph [00366] or paragraph [00367], wherein Z is Yx(Yxx)2(Yx)2Yxx, Yx(Yxx)2(Yx)2YxxY, Yx(Yxx)2(Yx)2YxxYx, Yx(Yxx)2(Yx)2(Yxx)2, Yx(Yxx)2(Yx)2(Yxx)2Y, Yx(Yxx)2(Yx)2(Yxx)2Yx, Uc(Ucc)2(Uc)2(Ucc)3, Yx(Yxx)2(Yx)2(Yxx)3Y, Yx(Yxx)2(Yx)2(Yxx)3Yx, or Yx(Yxx)2(Yx)2(Yxx)4.
[00369] The compound of any one of paragraphs [00366]-[00368], wherein each R1 is independently alkyl that is substituted and Ralpha1 is H, or each R1 is H and each Ralpha1 is independently alkyl that is substituted.
[00370] The compound of any one of paragraphs [00366]-[00368], wherein each R1 is independently alkyl that is substituted and Ralpha1 is H.
[00371] The compound of any one of paragraphs [00366]-[00368], wherein each R1 is H and each Ralpha1 is independently alkyl that is substituted.
[00372] The compound of any one of paragraphs [00356]-[00371], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N -methylguanidino group, or an amido group. [00373] The compound of any one of paragraphs [00356]-[00371], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2- thiomethyleth-l-yl, 4-aminobut-l-yl, 3-aminoprop-l-yl, l-H-imidazol-4-ylmethyl, 1 -H-indol-3- ylmethyl, benzyl, 4-hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3- guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00374] The compound of any one of paragraphs [00356]-[00371], wherein each alkyl that is substituted is independently a guanidinoalkyl group or a hydroxyalkyl group.
[00375] The compound of any one of paragraphs [00356]-[00371], wherein each alkyl that is substituted is hydroxymethyl.
[00376] The compound of any one of paragraphs [00356]-[00371], wherein each alkyl that is substituted is independently 3 -guani dinoprop- 1-yl, or 4-guanidinobut-l-yl.
[00377] The compound of any one of paragraphs [00356]-[00376], wherein each R2 is independently methyl substituted with the heterocycle.
[00378] The compound of any one of paragraphs [00356]-[00377], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[00379] The compound of paragraph [00352], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO: 1, PNA SEQ NO: 13, PNA SEQ NO: 17, PNA SEQ NO: 21, or PNA SEQ NO: 37.
[00380] The compound of paragraph [00352], wherein Z is a peptide nucleic acid sequence according to PNA SEQ NO: 2, PNA SEQ NO: 3, PNA SEQ NO: 4, PNA SEQ NO: 5, PNA SEQ NO: 6, PNA SEQ NO: 7, PNA SEQ NO: 8, PNA SEQ NO: 9, PNA SEQ NO: 10, PNA SEQ NO: 11, PNA SEQ NO: 15, PNA SEQ NO: 19, PNA SEQ NO: 23, PNA SEQ NO: 34, PNA SEQ NO: 25, PNA SEQ NO: 26, PNA SEQ NO: 27, PNA SEQ NO: 28, PNA SEQ NO: 29, PNA SEQ NO: 30, PNA SEQ NO: 31, PNA SEQ NO: 32, PNA SEQ NO: 33, or PNA SEQ NO: 36.
[00381] The compound of any one of paragraphs [00352] and [00356]-[00378], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases, wherein the nucleobases or analogues of nucleobases form a sequence complementary to a nucleic acid sequence selected from the group consisting of: CAGCAGCAGCAGC (SEQ ID NO: 99), CAGCAGCAGCAGCA (SEQ ID NO: 100), CAGCAGCAGCAGC AG (SEQ ID NO: 101), CAGCAGCAGCAGCAGC (SEQ ID NO: 102), CAGCAGCAGCAGCAGCA (SEQ ID NO: 103), CAGCAGCAGCAGCAGC AG (SEQ ID NO: 104), CAGCAGCAGCAGCAGCAGC (SEQ ID NO: 105), CAGCAGCAGCAGCAGCAGC A (SEQ ID NO: 106), CAGCAGCAGCAGCAGCAGC AG (SEQ ID NO: 107), CAGCAGCAGCAGC AGCAGCAGC (SEQ ID NO: 108), CAGCAGCAGCAGC AGCAGCAGC A (SEQ ID NO: 109), and C AGCAGCAGC AGCAGCAGC AGC AG (SEQ ID NO: 110).
[00382] A compound comprising a structure that is:
Figure imgf000121_0001
wherein: the first number of units with variables defined independently is at least zero; the second number of units with variables defined independently is at least 3; the third number of units with variables defined independently is at least zero; N -Terminus is H, acyl, a group that together with the nitrogen atom to which N -Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently alkyl that is unsubstituted or substituted or H; each R4 is independently R2; each R5 is independently alkyl that is unsubstituted or substituted or H; each R6 is independently R2; each R7 is independently alkyl that is unsubstituted or substituted or H; each R8 is independently R2, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha2 is independently alkyl that is unsubstituted or substituted or H; each Ralpha3 is independently alkyl that is unsubstituted or substituted or H; each Ralpha4 is independently alkyl that is unsubstituted or substituted or H;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[00383] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 3-1,000.
[00384] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 3-100.
[00385] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 3-50. [00386] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
[00387] The compound of paragraph [00382], wherein the first number of units with variables defined independently is zero.
[00388] The compound of paragraph [00382], wherein the first number of units with variables defined independently is at least 11.
[00389] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 11-1,000.
[00390] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 11-100.
[00391] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 11-50.
[00392] The compound of paragraph [00382], wherein the first number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00393] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3-1,000.
[00394] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3-100.
[00395] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3-50.
[00396] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00397] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00398] The compound of any one of paragraphs [00382]-[00392], wherein the second number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, or 10.
[00399] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 3-1,000.
[00400] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 3-100.
[00401] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 3-50.
[00402] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00403] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is zero.
[00404] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is at least 11.
[00405] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 11-1,000.
[00406] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 11-100.
[00407] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 11-50.
[00408] The compound of any one of paragraphs [00382]-[00398], wherein the third number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26, 27, 28, 29, or 30.
[00409] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is H. [00410] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is independently alkyl that is unsubstituted.
[00411] The compound of paragraph [00410], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00412] The compound of paragraph [00410], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00413] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is independently alkyl that is substituted.
[00414] The compound of paragraph [00413], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
[00415] The compound of paragraph [00413], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazol-4-ylmethyl, 1 -7/-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl. 100416] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is independently a guanidinoalkyl group or a hydroxyalkyl group.
[00417] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is hydroxymethyl.
[00418] The compound of any one of paragraphs [00382]-[00408], wherein each Ralpha1 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
[00419] The compound of any one of paragraphs [00382]-[00408], wherein at least one iteration 0f Ralphai is 3-guanidinoprop-l-yl.
[00420] The compound of any one of paragraphs [00382]-[00408], wherein at least a third of the iterations of Ralpha1 are 3-guanidinoprop-l-yl.
[00421] The compound of any one of paragraphs [00382]-[00408], wherein at least half the iterations of Ralpha1 are 3-guanidinoprop-l-yl.
[00422] The compound of any one of paragraphs [00382]-[00421], wherein each Ralphal is H. [00423] The compound of any one of paragraphs [00382]-[00421], wherein each Ralpha4 is independently alkyl that is unsubstituted.
[00424] The compound of paragraph [00423], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00425] The compound of paragraph [00423], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00426] The compound of any one of paragraphs [00382]-[00421], wherein each Ralpha4 is independently alkyl that is substituted.
[00427] The compound of paragraph [00426], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
[00428] The compound of paragraph [00426], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 H -imidazoM-ylmethyl, 1 - H -indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00429] The compound of any one of paragraphs [00382]-[00421], wherein each Ralpha4 is independently a guanidinoalkyl group or a hydroxyalkyl group.
[00430] The compound of any one of paragraphs [00382]-[00421], wherein each Ralpha4 is hydroxymethyl.
[00431] The compound of any one of paragraphs [00382]-[00421], wherein each Ralpha4 is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
[00432] The compound of any one of paragraphs [00382]-[00421], wherein at least one iteration of Ralpha4 3 -guanidinoprop- 1 -yl .
[00433] The compound of any one of paragraphs [00382]-[00421], wherein at least a third of the iterations of Ralpha4 are 3-guanidinoprop-l-yl.
[00434] The compound of any one of paragraphs [00382]-[00421], wherein at least half the iterations of Ralpha4 are 3-guanidinoprop-l-yl.
[00435] The compound of any one of paragraphs [00382]-[00434], wherein each R1 is independently alkyl that is unsubstituted.
[00436] The compound of paragraph [00435], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00437] The compound of paragraph [00435], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00438] The compound of any one of paragraphs [00382]-[00434], wherein each R1 is independently alkyl that is substituted.
[00439] The compound of paragraph [00438], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, N-methylguanidino group, or an amido group.
[00440] The compound of paragraph [00438], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00441] The compound of any one of paragraphs [00382]-[00434], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00442] The compound of any one of paragraphs [00382]-[00434] and [00438]-[00441], wherein at least one iteration of R1 is a hydroxyalkyl group.
[00443] The compound of any one of paragraphs [00382]-[00434] and [00438]-[00441], wherein at least one iteration of R1 is hydroxylmethyl.
[00444] The compound of any one of paragraphs [00382]-[00434] and [00438]-[00441], wherein at least a third of the iterations of R1 are hydroxylmethyl.
[00445] The compound of any one of paragraphs [00382]-[00434] and [00438]-[00441], wherein at least half the iterations of R1 are hydroxylmethyl.
[00446] The compound of any one of paragraphs [00382]-[00445], wherein each R7 is independently alkyl that is unsubstituted.
[00447] The compound of paragraph [00446], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00448] The compound of paragraph [00446], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00449] The compound of any one of paragraphs [00382]-[00445], wherein each R7 is independently alkyl that is substituted.
[00450] The compound of paragraph [00449], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a L'-methylguanidino group, or an amido group.
[00451] The compound of paragraph [00449], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00452] The compound of any one of paragraphs [00382]-[00445], wherein each R7 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00453] The compound of any one of paragraphs [00382]-[00445] and [00449]-[00451], wherein at least one iteration of R7 is a hydroxyalkyl group.
[00454] The compound of any one of paragraphs [00382]-[00445] and [00449]-[00451], wherein at least one iteration of R7 is hydroxylmethyl.
[00455] The compound of any one of paragraphs [00382]-[00445] and [00449]-[00451], wherein at least a third of the iterations of R7 are hydroxylmethyl.
[00456] The compound of any one of paragraphs [00382]-[00445] and [00449]-[00451], wherein at least half the iterations of R7 are hydroxylmethyl.
[00457] The compound of any one of paragraphs [00382]-[00456], wherein each R3 is independently an alkyl group that is unsubstituted or substituted, and each R5 is independently a group that is not substituted alkyl.
[00458] The compound of any one of paragraphs [00382]-[00456], wherein each R3 is independently a guanidinoalkyl group, and each R5 is independently a group that is not guanidinoalkyl.
[00459] The compound of any one of paragraphs [00382]-[00456], wherein each R3 is independently a hydroxyalkyl group, and each R5 is independently a group that is not hydroxyalkyl. [00460] The compound of any one of paragraphs [00382]-[00459], wherein each R3 is hydroxymethyl.
[00461] The compound of any one of paragraphs [00382]-[00460], wherein each R5 is H. [00462] The compound of any one of paragraphs [00382]-[00461], wherein each Ralpha2 and each Ralpha3 is H.
[00463] The compound of any one of paragraphs [00382]-[00456], wherein each Ralpha2 is independently an alkyl group that is unsubstituted or substituted, and Ralpha3 is independently a group that is not substituted alkyl.
[00464] The compound of any one of paragraphs [00382]-[00456], wherein each Ralpha2 is independently a guanidinoalkyl group, and each Ralpha3 is independently a group that is not guanidinoalkyl.
[00465] The compound of any one of paragraphs [00382]-[00456], wherein each Ralpha2 is independently a hydroxy alkyl group, and each Ralpha3 is independently a group that is not hydroxy alkyl.
[00466] The compound of any one of paragraphs [00463]-[00465], wherein each Ralpha2 is hydroxymethyl.
[00467] The compound of any one of paragraphs [00463]-[00466], wherein each Ralpha3 is H. [00468] The compound of any one of paragraphs [00463]-[00467], wherein each R3 and each R5 is H.
[00469] A compound comprising a structure that is:
Figure imgf000128_0001
wherein: the number of units with variables defined independently is at least 3;
.Y-Terminus is H, acyl, a group that together with the nitrogen atom to which N--Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle, wherein at least two R2 groups in the structure are independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof.
[00470] The compound of paragraph [00469], wherein the number of units with variables defined independently is 11-1,000.
[00471] The compound of paragraph [00469], wherein the number of units with variables defined independently is 11-100.
[00472] The compound of paragraph [00469], wherein the number of units with variables defined independently is 11-50.
[00473] The compound of paragraph [00469], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.
[00474] The compound of any one of paragraphs [00469]-[00473], wherein each Ralpha is H. [00475] The compound of any one of paragraphs [00469]-[00473], wherein each Ralpha is independently alkyl that is unsubstituted.
[00476] The compound of paragraph [00474], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00477] The compound of paragraph [00474], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00478] The compound of any one of paragraphs [00469]-[00473], wherein each Ralpha is independently alkyl that is substituted.
[00479] The compound of paragraph [00478], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, -NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, a N-methylguanidino group, or an amido group.
[00480] The compound of paragraph [00478], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazoM-ylmcthyl, 1 -H-indol-3-ylmcthyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00481] The compound of any one of paragraphs [00469]-[00473], wherein each Ralpha is independently H, 3-guanidinoprop-l-yl, or 4-guanidinobut-l-yl.
[00482] The compound of paragraph [00481], wherein at least one iteration of Ralpha is 3- guani dinoprop- 1 -yl .
[00483] The compound of paragraph [00481], wherein at least a third of the iterations of Ralpha are 3-guanidinoprop-l-yl.
[00484] The compound of paragraph [00481], wherein at least half the iterations of Ralpha are 3- guani dinoprop- 1 -yl .
[00485] The compound of any one of paragraphs [00469]-[00484], wherein the number of units with variables defined independently is at least 11; and at least one iteration of R1 is a hydroxy alkyl group.
[00486] The compound of paragraph [00469], wherein the number of units with variables defined independently is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein: a first unit is present or absent, and in the first unit:
Figure imgf000130_0001
a second unit is present or absent, and in the second unit:
Figure imgf000130_0002
a third unit is present, and in the third unit:
Figure imgf000131_0001
a fourth unit is present, and in the fourth unit:
R1 is H or -CH2OH; and R2 i iss
Figure imgf000131_0004
a fifth unit is present, and in the fifth unit:
Figure imgf000131_0002
a sixth unit is present, and in the sixth unit:
Figure imgf000131_0003
a seventh unit is present, and in the seventh unit:
R1 is H or -CH2OH; and R2 i iss
Figure imgf000131_0005
an eighth unit is present, and in the eighth unit:
Figure imgf000131_0006
a ninth unit is present, and in the ninth unit:
Figure imgf000132_0001
a tenth unit is present, and in the tenth unit:
Figure imgf000132_0002
an eleventh unit is present, and in the eleventh unit:
Figure imgf000132_0003
a twelfth unit is present, and in the twelfth unit:
Figure imgf000132_0004
a thirteenth unit is present, and in the thirteenth unit:
Figure imgf000132_0005
a fourteenth unit is present, and in the fourteenth unit:
Figure imgf000133_0001
a fifteenth unit is present or absent, and in the fifteenth unit:
Figure imgf000133_0002
a sixteenth unit is present or absent, and in the sixteenth unit:
Figure imgf000133_0003
a seventeenth unit is present or absent, and in the seventeenth unit:
Figure imgf000133_0004
an eighteenth unit is present or absent, and in the eighteenth unit:
Figure imgf000133_0005
nineteenth unit is present or absent, and in the nineteenth unit:
Figure imgf000133_0006
a twentieth unit is present or absent, and in the twentieth unit:
Figure imgf000134_0001
an twenty-first unit is present or absent, and in the twenty-first unit:
Figure imgf000134_0002
a twenty-second unit is present or absent, and in the twenty-second unit:
Figure imgf000134_0003
a twenty-third unit is present or absent, and in the twenty-third unit:
Figure imgf000134_0004
an twenty-fourth unit is present or absent, and in the twenty-fourth unit:
Figure imgf000134_0005
a twenty-fifth unit is present or absent, and in the twenty-fifth unit:
Figure imgf000135_0001
a twenty-sixth unit is present or absent, and in the twenty-sixth unit:
Figure imgf000135_0002
[00487] The compound of any one of paragraphs [00382]-[00486], wherein at least a third of the R2 groups in the structure are methyl substituted with a heterocycle.
[00488] The compound of any one of paragraphs [00382]-[00486], wherein at least half of the R2 groups in the structure are methyl substituted with a heterocycle.
[00489] The compound of any one of paragraphs [00382]-[00486], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[00490] The compound of any one of paragraphs [00382]-[00484], wherein at least one of the heterocycles of the R2 groups is a divalent nucleobase.
[00491] The compound of any one of paragraphs [00382]-[00484], wherein the heterocycles of the R2 groups are divalent nucleobases.
[00492] The compound of any one of paragraphs [00382]-[00489], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000135_0003
[00493] The compound of any one of paragraphs [00382]-[00489], wherein each R2 is independently: methyl,
Figure imgf000135_0004
[00494] The compound of any one of paragraphs [00473]-[00485], wherein of the units with variables defined independently, counting from N -Terminus, the first unit, the fourth unit, the seventh unit, the tenth unit, the thirteenth unit, the sixteenth unit, the nineteenth unit, the twenty - second unit, and the twenty-fifth unit, independently if present, each have
Figure imgf000136_0001
[00495] The compound of any one of paragraphs [00473]-[00485] and [00494], wherein of the units with variables defined independently, counting from N -Terminus, the second unit, the fifth unit, the eighth unit, the eleventh unit, the fourteenth unit, the seventeenth unit, the twentieth unit, the twenty-third unit, and the twenty-sixth unit, independently if present, each have
Figure imgf000136_0002
[00496] The compound of any one of paragraphs [00473]-[00485], [00494], and [00495], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty -fourth unit, independently if present, each have
Figure imgf000136_0003
[00497] The compound of any one of paragraphs [00473]-[00485] and [00494]-[00496], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the sixth unit, the ninth unit, the twelfth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty -fourth unit, independently if present, each have
Figure imgf000136_0004
[00498] The compound of any one of paragraphs [00473]-[00497], wherein of the units with variables defined independently, counting from N -Terminus, the second unit, the fourth unit, the sixth unit, the eighth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the eighteenth unit, the twentieth unit, the twenty-second unit, the twenty-fourth unit, and the twenty sixth unit, independently if present, each have hydrogen at R1.
[00499] The compound of any one of paragraphs [00473]-[00497], wherein of the units with variables defined independently, counting from N -Terminus, the fourth unit, the sixth unit, the seventh unit, the ninth unit, the tenth unit, the twelfth unit, the fourteenth unit, the sixteenth unit, the seventeenth unit, the nineteenth unit, the twentieth unit, the twenty-second unit, the twenty- third unit, the twenty-fifth unit, and the twenty-sixth unit, independently if present, each have hydrogen at R1.
[00500] The compound of any one of paragraphs [00473]-[00498], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty- fifth unit, independently if present, each have -CH2OH at R1.
[00501] The compound of any one of paragraphs [00473]-[00497] and [00499], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, and the twenty -fourth unit, independently if present, each have -CH2OH at R1.
[00502] The compound of any one of paragraphs [00469]-[00473] and [00486], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty- fifth unit, independently if present, each have -CH2OH at Ralpha.
[00503] The compound of any one of paragraphs [00469]-[00473] and [00486], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, and the twenty -fourth unit, independently if present, each have -CH2OH at
Ralpha
[00504] The compound of any one of paragraphs [00469]-[00473] and [00486], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty- fifth unit, independently if present, each have 3-guanidino-prop-l-yl at Ralpha.
[00505] The compound of any one of paragraphs [00469]-[00473] and [00486], wherein of the units with variables defined independently, counting from N- Terminus, the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty-first unit, and the twenty -fourth unit, independently if present, each have 3- guanidino-prop-l-yl at Ralpha.
[00506] The compound of any one of paragraphs [00469]-[00485], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the eighth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the eighteenth unit, the twenty -first unit, and the twenty -fourth unit, independently if present, each have 4-guanidino- but-l-yl at R1.
[00507] The compound of any one of paragraphs [00469]-[00485], wherein of the units with variables defined independently, counting from N -Terminus, the third unit, the fifth unit, the seventh unit, the ninth unit, the eleventh unit, the thirteenth unit, the fifteenth unit, the seventeenth unit, the nineteenth unit, the twenty-first unit, the twenty -third unit, and the twenty- fifth unit, independently if present, each have 4-guanidino-but-l-yl at R1.
[00508] The compound of any one of paragraphs [00469]-[00485], wherein of the units with variables defined independently, counting from N -Terminus, the first, third, sixth, ninth, eleventh, thirteenth, sixteenth, nineteenth, and twenty-second units, independently if present, each have 3 -guanidinoprop- 1-yl at Ralpha.
[00509] The compound of any one of paragraphs [00469]-[00484], wherein each R1 is independently alkyl that is unsubstituted.
[00510] The compound of paragraph [00509], wherein each alkyl that is unsubstituted is independently methyl, ethyl, prop-l-yl, prop-2-yl, 2-methylprop-l-yl, but-lyl, but-2-yl, or pent- 1-yl.
[00511] The compound of paragraph [00509], wherein each alkyl that is unsubstituted is independently methyl, prop-2-yl, 2-methylprop-l-yl, orbut-2-yl.
[00512] The compound of any one of paragraphs [00469]-[00484], wherein each R1 is independently alkyl that is substituted.
[00513] The compound of paragraph [00512], wherein each alkyl that is substituted is independently substituted with -OH, -SH, -SMe, - NH2, a heterocycle, an aryl group, a carboxylic acid, a guanidino group, aN -methylguanidino group, or an amido group.
[00514] The compound of paragraph [00512], wherein each alkyl that is substituted is independently hydroxymethyl, 1-hydroxyeth-l-yl, sulfhydrylmethyl, 2-thiomethyleth-l-yl, 4- aminobut-l-yl, 3-aminoprop-l-yl, 1 -H-imidazol-4-ylmethyl, 1 -H-indol-3-ylmethyl, benzyl, 4- hydroxyphen-l-ylmethyl, 2-carboxylatoeth-l-yl, 3-carboxylatoprop-l-yl, 3-guanidinoprop-l-yl, 4-guanidinobut-l-yl, 2-carbamoyleth-l-yl, or 3-carbamoylprop-l-yl.
[00515] The compound of any one of paragraphs [00469]-[00484], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00516] The compound of any one of paragraphs [00469]-[00484], wherein at least one iteration of R1 is a hydroxy alkyl group.
[00517] The compound of any one of paragraphs [00469]-[00484], wherein at least one iteration of R1 is hydroxylmethyl.
[00518] The compound of paragraph [00516], wherein at least a third of the iterations of R1 are hydroxylmethyl.
[00519] The compound of paragraph [00516], wherein at least half the iterations of R1 are hydroxylmethyl.
[00520] The compound of any one of paragraphs [00352]-[00519], wherein PEP1 is absent. [00521] The compound of any one of paragraphs [00352]-[00519], wherein PEP1 is the peptide sequence.
[00522] The compound of any one of paragraphs [00352]-[00519] and [00521], wherein the peptide sequence of PEP1 is a nuclear localization sequence.
[00523] The compound of any one of paragraphs [00352]-[00519] and [00521], wherein at least one of PEP1 and PEP2 is a peptide sequence of at least three amino acid residues.
[00524] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is -Lys-.
[00525] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is -(/9-Lys)-.
[00526] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -(/9-Arg)-(/9-Arg)-(/9-Arg)-(/4-Arg)- (SEQ ID NO: 181). [00527] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149).
[00528] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148). [00529] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141).
[00530] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is -Cys'-Leu-Ser-Ser-Arg-Leu-Asp-Ala-Cys2- , wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142). [00531] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Cys1-Ala-Gly-Ala-Leu-Cys2-Tyr-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143).
[00532] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Cys'-Lcu-Glu-Val-Scr-Arg-Lys-Asn-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144).
[00533] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Cys'-Arg-Thr-Ilc-Gly-Pro-Scr-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82).
[00534] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145).
[00535] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146).
[00536] The compound of any one of paragraphs [00352]-[00519], [00521], and [00523], wherein PEP1 is a sequence that is -Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147).
[00537] The compound of any one of paragraphs [00352]-[00536], wherein PEP2 is absent. [00538] The compound of any one of paragraphs [00352]-[00536], wherein PEP2 is the peptide sequence.
[00539] The compound of any one of paragraphs [00352]-[00536] or [00538], wherein the peptide sequence of PEP2 is a nuclear localization sequence.
[00540] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is -Lys-.
[00541] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is -(D-Lys)-.
[00542] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -(/9-Arg)-(/9-Arg)-(/9-Arg)-(/9-Arg)- (SEQ ID NO: 181).
[00543] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is -Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg- (SEQ ID NO: 149).
[00544] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg- (SEQ ID NO: 148).
[00545] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Leu-Cys-Leu-Arg-Pro-Val-Gly- (SEQ ID NO: 141). [00546] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys'-Lcu-Scr-Scr-Arg-Lcu-Asp-Ala-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 142).
[00547] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys1-Ala-Gly-Ala-Leu-Cys2-Tyr-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 143).
[00548] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys'-Lcu-Glu-Val-Scr-Arg-Lys-Asn-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 144).
[00549] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys'-Arg-Thr-Ile-Gly-Pro-Ser-Val-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 82).
[00550] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys'-Thr-Ser-Thr-Ser-Ala-Pro-Tyr-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 145).
[00551] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is -Cys'-Met-Pro-Arg-Leu-Arg-Gly-Cys2-, wherein Cys1 and Cys2 are bound to one another via an intrachain disulfide bond (SEQ ID NO: 146).
[00552] The compound of any one of paragraphs [00352]-[00536] and [00538], wherein PEP2 is a sequence that is Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly- (SEQ ID NO: 147). [00553] The compound of any one of paragraphs [00352]-[00552], wherein SOL1 is absent. [00554] The compound of any one of paragraphs [00352]-[00552], wherein SOL1 is the water- solubilizing group.
[00555] The compound of any one of paragraphs [00352]-[00552] and [00554], wherein the water-solubilizing group of SOL1 is a peptide sequence.
[00556] The compound of any one of paragraphs [00352]-[00552], [00554], and [00555], wherein the water-solubilizing group of SOL1 is a group that contains multiple electrical charges at physiological pH.
[00557] The compound of any one of paragraphs [00352]-[00552] and [00554]-[00556], wherein the water-solubilizing group of SOL1 is a group that contains multiple positive charges at physiological pH.
[00558] The compound of any one of paragraphs [00352]-[00552] and [00554], wherein the water-solubilizing group of SOL1 is a polyethyleneglycol group.
[00559] The compound of any one of paragraphs [00352]-[00552] and [00554], wherein the water-solubilizing group of SOL1 is -Arg-Arg-NH(CH2)2C(0)-Arg-Arg- (SEQ ID NO: 136). [00560] The compound of any one of paragraphs [00352]-[00552] and [00554], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000142_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00561] The compound of any one of paragraphs [00352]-[00552], [00554], and [00560], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000142_0002
wherein p is an integer that is 1-1,000.
[00562] The compound of any one of paragraphs [00352]-[00552] and [00554], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000142_0003
, wherein Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00563] The compound of any one of paragraphs [00352]-[00552], [00554], and [00560]- [00562], wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000143_0001
wherein p is an integer that is 1-1,000.
[00564] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 1-100.
[00565] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 1-50.
[00566] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00567] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[00568] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10.
[00569] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 5, 6, 7, 8, or 9.
[00570] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 6, 7, or 8. [00571] The compound of any one of paragraphs [00560]-[00563], wherein p is an integer that is 7.
[00572] The compound of any one of paragraphs [00352]-[00570], wherein SOL2 is absent [00573] The compound of any one of paragraphs [00352]-[00570], wherein SOL2 is the water- solubilizing group.
[00574] The compound of any one of paragraphs [00352]-[00570] and [00573], wherein the water-solubilizing group of SOL2 is a peptide sequence.
[00575] The compound of any one of paragraphs [00352]-[00570], [00573], and [00574], wherein the water-solubilizing group of SOL2 is a group that contains multiple electrical charges at physiological pH.
[00576] The compound of any one of paragraphs [00352]-[00570], and [00573]-[00575], wherein the water-solubilizing group of SOL2 is a group that contains multiple positive charges at physiological pH.
[00577] The compound of any one of paragraphs [00352]-[00570] and [00573], wherein the water-solubilizing group of SOL2 is a polyethyleneglycol group.
[00578] The compound of any one of paragraphs [00352]-[00570] and [00573], wherein the water-solubilizing group of SOL2 is -Arg-Arg-NH(CH2)2C(O)-Arg-Arg- (SEQ ED NO: 136). [00579] The compound of any one of paragraphs [00352]-[00570] and [00573], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000144_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00580] The compound of any one of paragraphs [00352]-[00570], [00573], and [00579], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000145_0001
wherein p is an integer that is 1-1,000.
[00581] The compound of any one of paragraphs [00352]-[00570] and [00573], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000145_0002
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O- heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), or N(PgN); n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000.
[00582] The compound of any one of paragraphs [00352]-[00570], [00573], and [00579]- [00581], wherein the water-solubilizing group of SOL2 is a group of formula:
Figure imgf000146_0001
wherein p is an integer that is 1-1,000.
[00583] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 1-100.
[00584] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 1-50.
[00585] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[00586] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
[00587] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 3, 4, 5, 6, 7, 8, 9, or 10.
[00588] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 5, 6, 7, 8, or 9.
[00589] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 6, 7, or 8.
[00590] The compound of any one of paragraphs [00579]-[00582], wherein p is an integer that is 7.
[00591] The compound of any one of paragraphs [00352]-[00590], wherein PNA1 is the peptide nucleic acid sequence.
[00592] The compound of any one of paragraphs [00352]-[00591], wherein PNA2 is the peptide nucleic acid sequence.
[00593] The compound of any one of paragraphs [00352]-[00592], wherein L1 is the linker group.
[00594] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is cleavable.
[00595] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is non-cleavable.
[00596] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is a peptide sequence. [00597] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is a polyamine sequence.
[00598] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is a polyamide sequence.
[00599] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is a residue of an omega-amino fatty acid.
[00600] The compound of any one of paragraphs [00352]-[00593] and [00599], wherein the linker group of L1 is a residue of an omega-amino caproic acid.
[00601] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is a residue of a dicarboxylic acid.
[00602] The compound of any one of paragraphs [00352]-[00593] and [00601], wherein the linker group of L1 is a residue of oxalic acid.
[00603] The compound of any one of paragraphs [00352]-[00593] and [00601], wherein the linker group of L1 is a residue of succinic acid.
[00604] The compound of any one of paragraphs [00352]-[00593], [00596], and [00598], wherein the linker group of L1 is a peptide sequence that is -Glu-Val-Citrulline-.
[00605] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00606] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00607] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00608] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00609] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -Arg-NH(CH2)5C(0)-.
[00610] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2)5C(0)-.
[00611] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00612] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L 1 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-.
[00613] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(0)-Arg-Arg-NH(CH2)5C(0)- (SEQ ID NO: 137). [00614] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -MT(CH2)5C(0)NH(CH2)2-(D-argininc)-(D-argininc)-(D)-argininc)-.
[00615] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -M1(CH2CH20)2CH2C(0)-.
[00616] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00617] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00618] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00619] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-.
[00620] The compound of any one of paragraphs [00352]-[00593], wherein the linker group of L1 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-,
[00621] The compound of any one of paragraphs [00352]-[00593], [00596], and [00598], wherein the linker group of L1 is a peptide sequence that is -Lys-.
[00622] The compound of any one of paragraphs [00352]-[00593], [00596], and [00598], wherein the linker group of L1 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-. [00623] The compound of any one of paragraphs [00352]-[00622], wherein L2 is the linker group.
[00624] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is cleavable.
[00625] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is non-cleavable.
[00626] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is a peptide sequence.
[00627] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is a polyamine sequence.
[00628] The compound of any one of paragraphs [00352]-[00623] and [00626], wherein the linker group of L2 is a polyamide sequence.
[00629] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is a residue of an omega-amino fatty acid.
[00630] The compound of any one of paragraphs [00352]-[00623] and [00629], wherein the linker group of L2 is a residue of an omega-amino caproic acid.
[00631] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is a residue of a dicarboxylic acid.
[00632] The compound of any one of paragraphs [00352]-[00623] and [00631], wherein the linker group of L2 is a residue of oxalic acid.
[00633] The compound of any one of paragraphs [00352]-[00623] and [00631], wherein the linker group of L2 is a residue of succinic acid.
[00634] The compound of any one of paragraphs [00352]-[00623] and [00626], wherein the linker group of L2 is a peptide sequence that is -Glu-Val-Citrulline-.
[00635] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00636] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00637] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00638] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00639] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -Arg-NH(CH2)5C(0)-.
[00640] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2)5C(0)-.
[00641] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00642] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2)5C(0)-Arg-M1(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-.
[00643] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(0)-Arg-Arg-NH(CH2)5C(0)- (SEQ ID NO: 137).
[00644] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2)5C(0)NH(CH2)2-(D-arginine)-(D-arginine)-(D-arginine)-.
[00645] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-.
[00646] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00647] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00648] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00649] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-.
[00650] The compound of any one of paragraphs [00352]-[00623], wherein the linker group of L2 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-.
[00651] The compound of any one of paragraphs [00352]-[00623] and [00626], wherein the linker group of L2 is a peptide sequence that is -Lys-.
[00652] The compound of any one of paragraphs [00352]-[00623] and [00626], wherein the linker group of L2 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00653] The compound of any one of paragraphs [00352]-[00652], wherein L3 is the linker group.
[00654] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is cleavable.
[00655] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is non-cleavable.
[00656] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is a peptide sequence.
[00657] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is a polyamine sequence.
[00658] The compound of any one of paragraphs [00352]-[00653] and [00656], wherein the linker group of L3 is a polyamide sequence.
[00659] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is a residue of an omega-amino fatty acid.
[00660] The compound of any one of paragraphs [00352]-[00653] and [00659], wherein the linker group of L3 is a residue of an omega-amino caproic acid.
[00661] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is a residue of a dicarboxylic acid.
[00662] The compound of any one of paragraphs [00352]-[00653] and [00661], wherein the linker group of L3 is a residue of oxalic acid.
[00663] The compound of any one of paragraphs [00352]-[00653] and [00661], wherein the linker group of L3 is a residue of succinic acid.
[00664] The compound of any one of paragraphs [00352]-[00653] and [00656], wherein the linker group of L3 is a peptide sequence that is -Glu-Val-Citrulline-.
[00665] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-. [00666] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00667] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00668] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00669] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -Arg-NH(CH2)5C(0)-.
[00670] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2)5C(0)-.
[00671] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00672] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-.
[00673] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(0)-Arg-Arg-NH(CH2)5C(0)- (SEQ ID NO: 137).
[00674] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2)5C(0)NH(CH2)2-(D-arginine)-(D-arginine)-(Z)-arginine)-.
[00675] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-.
[00676] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00677] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00678] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00679] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-,
[00680] The compound of any one of paragraphs [00352]-[00653], wherein the linker group of L3 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-,
[00681] The compound of any one of paragraphs [00352]-[00653] and [00656], wherein the linker group of L3 is a peptide sequence that is -Lys-.
[00682] The compound of any one of paragraphs [00352]-[00653] and [00656], wherein the linker group of L3 is a peptide sequence that is -(D-Arg)-(70-Arg)-(70-Arg)-. [00683] The compound of any one of paragraphs [00352]-[00682], wherein L4 is the linker group.
[00684] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is cleavable.
[00685] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is non-cleavable.
[00686] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is a peptide sequence.
[00687] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is a polyamine sequence.
[00688] The compound of any one of paragraphs [00352]-[00683] and [00686], wherein the linker group of L4 is a polyamide sequence.
[00689] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is a residue of an omega-amino fatty acid.
[00690] The compound of any one of paragraphs [00352]-[00683] and [00689], wherein the linker group of L4 is a residue of an omega-amino caproic acid.
[00691] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is a residue of a dicarboxylic acid.
[00692] The compound of any one of paragraphs [00352]-[00683] and [00691], wherein the linker group of L4 is a residue of oxalic acid.
[00693] The compound of any one of paragraphs [00352]-[00683] and [00691], wherein the linker group of L4 is a residue of succinic acid.
[00694] The compound of any one of paragraphs [00352]-[00683] and [00686], wherein the linker group of L4 is a peptide sequence that is -Glu-Val-Citrulline-.
[00695] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00696] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00697] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00698] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -Lys-NHCH(COOH)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00699] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -Arg-NH(CH2)5C(0)-.
[00700] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2)5C(0)-.
[00701] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00702] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00703] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(0)-Arg-Arg-NH(CH2)5C(0)- (SEQ ID NO: 137).
[00704] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2)5C(0)NH(CH2)2-(D-arginine)-(D-arginine)-(Z)-arginine)-.
[00705] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-.
[00706] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00707] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00708] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00709] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-.
[00710] The compound of any one of paragraphs [00352]-[00683], wherein the linker group of L4 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-,
[00711] The compound of any one of paragraphs [00352]-[00683] and [00686], wherein the linker group of L4 is a peptide sequence that is -Lys-.
[00712] The compound of any one of paragraphs [00352]-[00683] and [00686], wherein the linker group of L4 is a peptide sequence that is -(D-Arg)-(D-Arg)-(D-Arg)-.
[00713] The compound of any one of paragraphs [00352]-[00712], wherein L5 is the linker group.
[00714] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is cleavable.
[00715] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is non-cleavable.
[00716] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is a peptide sequence.
[00717] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is a polyamine sequence.
[00718] The compound of any one of paragraphs [00352]-[00713] and [00716], wherein the linker group of L5 is a polyamide sequence.
[00719] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is a residue of an omega-amino fatty acid.
[00720] The compound of any one of paragraphs [00352]-[00713], and [00719], wherein the linker group of L5 is a residue of an omega-amino caproic acid.
[00721] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is a residue of a dicarboxylic acid.
[00722] The compound of any one of paragraphs [00352]-[00713] and [00721], wherein the linker group of L5 is a residue of oxalic acid.
[00723] The compound of any one of paragraphs [00352]-[00713] and [00721], wherein the linker group of L5 is a residue of succinic acid.
[00724] The compound of any one of paragraphs [00352]-[00713] and [00716], wherein the linker group of L5 is a peptide sequence that is -Glu-Val-Citrulline-.
[00725] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00726] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00727] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00728] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(Ml2)C(0)-.
[00729] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -Arg-NH(CH2)5C(0)-.
[00730] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2)5C(0)-.
[00731] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00732] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-.
[00733] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2)3C(O)NH(CH2)>-(D -arginine)-(D-arginine)-(79-arginine)-.
[00734] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-. [00735] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00736] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00737] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00738] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-.
[00739] The compound of any one of paragraphs [00352]-[00713], wherein the linker group of L5 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-.
[00740] The compound of any one of paragraphs [00352]-[00713] and [00716], wherein the linker group of L5 is a peptide sequence that is -Lys-.
[00741] The compound of any one of paragraphs [00352]-[00740], wherein L6 is the linker group.
[00742] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is cleavable.
[00743] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is non-cleavable.
[00744] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is a peptide sequence.
[00745] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is a polyamine sequence.
[00746] The compound of any one of paragraphs [00352]-[00741] and [00744], wherein the linker group of L6 is a polyamide sequence.
[00747] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is a residue of an omega-amino fatty acid.
[00748] The compound of any one of paragraphs [00352]-[00741] and [00747], wherein the linker group of L6 is a residue of an omega-amino caproic acid.
[00749] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is a residue of a dicarboxylic acid.
[00750] The compound of any one of paragraphs [00352]-[00741] and [00749], wherein the linker group of L6 is a residue of oxalic acid.
[00751] The compound of any one of paragraphs [00352]-[00741] and [00749], wherein the linker group of L6 is a residue of succinic acid.
[00752] The compound of any one of paragraphs [00352]-[00741] and [00744], wherein the linker group of L6 is a peptide sequence that is -Glu-Val-Citrulline-.
[00753] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-
[00754] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00755] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -Lys-NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-.
[00756] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -Lys-NHCH(C00H)C(CH3)2S-SCH2CH(NH2)C(0)-.
[00757] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -Arg-NH(CH2)5C(0)-.
[00758] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2)5C(0)-.
[00759] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2)2C(0)-Arg-NH(CH2)5C(0)NH(CH2)2C(0)-.
[00760] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2)5C(0)-Arg-NH(CH2)2C(0)-Arg-NH(CH2)5C(0)-Arg-NH(CH2)2C(0).
[00761] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -Arg-NH(CH2)5C(0)-Arg-Arg-NH(CH2)2C(0)-Arg-Arg-NH(CH2)5C(0)- (SEQ ID NO: 137).
[00762] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -M4(CH2)5C(0)NH(CH2)2-(/4-arginine)-(/J-arginine)-(/)-arginine)-.
[00763] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-.
[00764] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-Arg-.
[00765] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00766] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-.
[00767] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-Arg-Arg-.
[00768] The compound of any one of paragraphs [00352]-[00741], wherein the linker group of L6 is -NH(CH2CH20)2CH2C(0)-Arg-NH(CH2CH20)2CH2C(0)-Arg-.
[00769] The compound of any one of paragraphs [00352]-[00741] and [00744], wherein the linker group of L6 is a peptide sequence that is -Lys-.
[00770] The compound of any one of paragraphs [00352]-[00741] and [00744], wherein the linker group of L6 is a peptide sequence that is -(H-Arg)-(D-Arg)-(D-Arg)-.
[00771] The compound of any one of paragraphs [00352]-[00486], wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP1, SOL1, and SOL2 is absent.
[00772] The compound of any one of paragraphs [00469]-[00486], wherein the structure is:
Figure imgf000157_0002
wherein the number of units with variables defined independently is at least 11; or a pharmaceutically-acceptable salt or ionized form thereof.
[00773] The compound of any one of paragraphs [00469]-[00486] and [00772], wherein the structure is:
Figure imgf000157_0001
or a pharmaceutically-acceptable salt or ionized form thereof.
[00774] The compound of paragraph [00772] or paragraph [00773], wherein at least one iteration of R1 is a hydroxyalkyl group.
[00775] The compound of any one of paragraphs [00352]-[00774], wherein A/-Terminus is H. [00776] The compound of any one of paragraphs [00352]-[00774], wherein A-Terminus is acyl. [00777] The compound of any one of paragraphs [00352]-[00774], wherein A-Terminus is the biological agent.
[00778] The compound of paragraph [00777], wherein the biological agent is a vitamin E group. [00779] The compound of paragraph [00777], wherein the biological agent is an O-bound tocopherol group.
[00780] The compound of any one of paragraphs [00352]-[00779], wherein C-Terminus is OH, O-alkyl, orME.
[00781] The compound of any one of paragraphs [00352]-[00779], wherein C-Terminus is OH, OMe, OEt, 0/-Bu, or NH2.
[00782] The compound of any one of paragraphs [00352]-[00779], wherein C-Terminus is NH2. [00783] The compound of any one of paragraphs [00352]-[00779], wherein C-Terminus is the peptide sequence.
[00784] The compound of any one of paragraphs [00352]-[00779], wherein C-Terminus is a peptide sequence according to SEQ ID NO: 1, wherein the C-terminal residue of the peptide sequence is amidated.
[00785] A compound comprising a repeating unit of formula:
Figure imgf000158_0001
wherein: each R1 is independently a hydroxyalkyl group; each R2 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each R3 is independently a group that is not hydroxyalkyl; each R4 is independently alkyl, O-alkyl, or methyl substituted with a heterocycle; each Ralpha1 is independently alkyl that is unsubstituted or substituted or H; and each Ralpha2 is independently alkyl that is unsubstituted or substituted or H, wherein the repeating unit occurs at least twice consecutively in the compound.
[00786] The compound of paragraph [00785], wherein each R1 is independently an alkyl group that is unsubstituted or substituted, and each R3 is independently a group that is not substituted alkyl.
[00787] The compound of paragraph [00785], wherein each R1 is independently a guanidinoalkyl group, and each R3 is independently a group that is not guanidinoalkyl.
[00788] The compound of paragraph [00785], wherein each R1 is independently a hydroxyalkyl group, and each R3 is independently a group that is not hydroxyalkyl.
[00789] The compound of any one of paragraphs [00785]-[00788], wherein each R1 is hydroxymethyl.
[00790] The compound of any one of paragraphs [00785]-[00789], wherein each R3 is H. [00791] The compound of any one of paragraphs [00785]-[00790], wherein each Ralpha1 and each Ralpha2 is H.
[00792] The compound of paragraph [00785], wherein each Ralpha1 is independently an alkyl group that is unsubstituted or substituted, and Ralpha2 is independently a group that is not substituted alkyl.
[00793] The compound of paragraph [00785], wherein each Ralpha1 is independently a guanidinoalkyl group, and each Ralpha2 is independently a group that is not guanidinoalkyl. [00794] The compound of paragraph [00785], wherein each Ralpha1 is independently a hydroxyalkyl group, and each Ralpha2 is independently a group that is not hydroxyalkyl.
[00795] The compound of any one of paragraphs [00792]-[00794], wherein each Ralpha1 is hydroxymethyl.
[00796] The compound of any one of paragraphs [00792]-[00795], wherein each Ralpha2 is H. [00797] The compound of any one of paragraphs [00792]-[00796], wherein each R1 and each R3 is H.
[00798] The compound of any one of paragraphs [00785]-[00797], wherein the repeating unit occurs at least five times consecutively in the compound.
[00799] The compound of any one of paragraphs [00785]-[00797], wherein the repeating unit occurs at least seven times consecutively in the compound.
[00800] The compound of any one of paragraphs [00785]-[00799], wherein at least a third of the R2 groups in the structure are methyl substituted with a heterocycle.
[00801] The compound of any one of paragraphs [00785]-[00799], wherein at least half of the R2 groups in the structure are methyl substituted with a heterocycle.
[00802] The compound of any one of paragraphs [00785]-[00801], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[00803] The compound of any one of paragraphs [00785]-[00802], wherein at least one of the heterocycles of the R2 groups is a divalent nucleobase.
[00804] The compound of any one of paragraphs [00785]-[00803], wherein the heterocycles of the R2 groups are divalent nucleobases.
[00805] The compound of any one of paragraphs [00785]-[00801], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000159_0001
[00806] The compound of any one of paragraphs [00785]-[00801], wherein each R2 is independently: methyl,
Figure imgf000159_0002
[00807] The compound of any one of paragraphs [00785]-[00806], wherein at least a third of the R4 groups in the structure are methyl substituted with a heterocycle.
[00808] The compound of any one of paragraphs [00785]-[00806], wherein at least half of the R4 groups in the structure are methyl substituted with a heterocycle.
[00809] The compound of any one of paragraphs [00785]-[00806], wherein the heterocycles of the R4 groups are nucleobases or analogues of nucleobases.
[00810] The compound of any one of paragraphs [00785]-[00806], wherein at least one of the heterocycles of the R4 groups is a divalent nucleobase.
[00811] The compound of any one of paragraphs [00785]-[00806], wherein the heterocycles of the R4 groups are divalent nucleobases.
[00812] The compound of any one of paragraphs [00785]-[00806], wherein the heterocycles of the R4 groups are each independently:
Figure imgf000160_0001
[00813] The compound of any one of paragraphs [00785]-[00806], wherein each R4 is independently: methyl,
Figure imgf000160_0002
[00814] The compound of any one of paragraphs [00352]-[00813], wherein the structure binds to a mRNA sequence transcribed from a gene associated with a neurodegenerative disease phenotype.
[00815] The compound of any one of paragraphs [00352]-[00813], wherein the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype. [00816] The compound of any one of paragraphs [00352]-[00813], wherein the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of the Huntington’s gene.
[00817] The compound of paragraph [00815] or paragraph [00816], wherein the Huntington’s gene is a non-wild type HTT gene. [00818] The compound of paragraph [00817], wherein the non-wild type HTT gene differs from a wild type HTT gene in a repeat expansion mutation.
[00819] The compound of any one of paragraphs [00352]-[00818], wherein the structure binds to a mRNA sequence that contains a subsequence that is (CAG)Z, wherein z is an integer from 1- 100 (SEQ ID NO: 135).
[00820] The compound of paragraph [00819], wherein the structure binds to the mRNA sequence at the subsequence that is (CAG)Z (SEQ ID NO: 135).
[00821] A compound comprising
1) a region that comprises a structure that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the region that comprises the structure that interferes with expression of the gene associated with a neurodegenerative disease phenotype an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000161_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O- alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O- alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof. [00822] The compound of paragraph [00821], wherein n is 3. [00823] The compound of paragraph [00821], wherein n is 4.
[00824] The compound of any one of paragraphs [00821]-[00823], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[00825] The compound of any one of paragraphs [00821]-[00823], wherein R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, or heterocyclyl.
[00826] The compound of any one of paragraphs [00821]-[00823], wherein R5 is linear alkyl, branched alkyl, or cyclic alkyl.
[00827] The compound of any one of paragraphs [00821]-[00823], wherein R5 is linear alkyl. [00828] The compound of any one of paragraphs [00821]-[00823], wherein R5 is methyl. [00829] The compound of paragraph [00821], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype..
[00830] The compound of paragraph [00829], wherein the structure is a oligonucleotide or oligonucleotide analogue.
[00831] The compound of paragraph [00829], wherein the structure is a peptide nucleic acid. [00832] A compound comprising a first chemical moiety, a pharmacophore, and a nitrogen- containing group, wherein the first chemical moiety, the pharmacophore, and the branched group form:
Figure imgf000162_0001
, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, heterocyclyl, linear O-alkyl, branched O-alkyl, cyclic O-alkyl, linear O-alkenyl, branched O-alkenyl, cyclic O-alkenyl, linear O-alkynyl, branched O-alkynyl, cyclic O-alkynyl, O-aryl, O-heteroaryl, or O-heterocyclyl any of which is unsubstituted or substituted;
Q is O, NH, N(alkyl), orN(PgN);
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-1,000, or a pharmaceutically-acceptable salt or ionized form thereof.
[00833] The compound of paragraph [00832], wherein R5 is linear alkyl, branched alkyl, cyclic alkyl, linear alkenyl, branched alkenyl, cyclic alkenyl, linear alkynyl, branched alkynyl, cyclic alkynyl, aryl, heteroaryl, or heterocyclyl.
[00834] The compound of paragraph [00832], wherein R5 is linear alkyl, branched alkyl, or cyclic alkyl.
[00835] The compound of paragraph [00832], wherein R5 is linear alkyl.
[00836] The compound of paragraph [00832], wherein R5 is methyl.
[00837] The compound of any one of paragraphs [00832]-[00836], wherein Q is NH or N(PgN). [00838] The compound of any one of paragraphs [00832]-[00837], wherein n is 3.
[00839] The compound of any one of paragraphs [00832]-[00837], wherein n is 4.
[00840] The compound of any one of paragraphs [00832]-[00839], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[00841] The compound of any one of paragraphs [00832]-[00839], wherein p is from 1 to 100 [00842] The compound of any one of paragraphs [00832]-[00839], wherein p is 5, 6, 7, 8, or 9. [00843] The compound of any one of paragraphs [00832]-[00842], wherein E1 is the first chemical moiety or the pharmacophore, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a linker, a probe, a metal chelator, or an imaging agent,.
[00844] The compound of any one of paragraphs [00832]-[00843], wherein E1 is the pharmacophore.
[00845] The compound of any one of paragraphs [00832]-[00843], wherein E1 is hydrogen. [00846] The compound of any one of paragraphs [00832]-[00845], wherein E2 is the first chemical moiety or the pharmacophore, wherein the first chemical moiety is OH, O-alkyl, ME, a linker, a probe, a metal chelator, or an imaging agent.
[00847] The compound of any one of paragraphs [00832]-[00845], wherein E2 is the pharmacophore.
[00848] The compound of any one of paragraphs [00832]-[00845], wherein E2 is OH or ME. [00849] The compound of any one of paragraphs [00843], [00844], [00846], and [00847], wherein the pharmacophore comprises a structure that interferes with expression of a gene associated with a neurodegenerative disease phenotype.
[00850] The compound of any one of paragraphs [00843], [00844], [00846], [00847], and [00849], wherein the pharmacophore is a oligonucleotide or oligonucleotide analogue.
[00851] The compound of any one of paragraphs [00843], [00844], [00846], [00847], and [00849], wherein the pharmacophore is a peptide nucleic acid.
[00852] The compound of any one of paragraphs [00829]-[00831] and [00849], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00853] The compound of any one of paragraphs [00829]-[00831] and [00849], wherein the structure binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
[00854] The compound of paragraph [00853], wherein the gene associated with a Huntington’s disease phenotype is a non-wild type HTT gene.
[00855] The compound of paragraph [00854], wherein the non-wild type HTT gene differs from a wild type HTT gene in a repeat expansion mutation.
[00856] The compound of any one of paragraphs [00829]-[00831] and [00849], wherein the structure binds to a mRNA sequence that contains a subsequence that is (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
[00857] The compound of paragraph [00856], wherein the structure binds to the mRNA sequence at the subsequence that is (CAG)Z.
[00858] A composition comprising a compound according to any one of paragraphs [00352]- [00857], wherein the compound is therapeutically-effective for treatment of a neurodegenerative disease.
[00859] The composition of paragraph [00858], wherein the neurodegenerative disease is Huntington’s disease.
[00860] A compound comprising:
1) a pharmacophore that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000165_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[00861] The compound of paragraph [00860], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[00862] The compound of paragraph [00860] or paragraph [00861], wherein R5 is linear alkyl. [00863] The compound of paragraph [00860] or paragraph [00861], wherein R5 is methyl. [00864] The compound of any one of paragraphs [00860]-[00863], wherein n is 3.
[00865] The compound of any one of paragraphs [00860]-[00863], wherein n is 4.
[00866] The compound of paragraph [00860], further comprising a first chemical moiety attached to the oligomeric structure, wherein the oligomeric structure, the first chemical moiety, and the pharmacophore form:
Figure imgf000165_0002
wherein:
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; and p is an integer that is 1-100.
[00867] The compound of paragraph [00866], wherein p is 6.
[00868] The compound of paragraph [00866], wherein p is 7.
[00869] The compound of paragraph [00866], wherein p is 8.
[00870] The compound of any one of paragraphs [00866]-[00869], wherein E1 is the first chemical moiety, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a probe, a metal chelator, or an imaging agent; and E2 is the pharmacophore.
[00871] The compound of any one of paragraphs [00866]-[00870], wherein E1 is an acyl group, and E2 is the pharmacophore.
[00872] The compound of any one of paragraphs [00866]-[00870], wherein E1 is acetyl, E2 is the pharmacophore.
[00873] The compound of any one of paragraphs [00866]-[00870], wherein E1 is hydrogen and E2 is the pharmacophore.
[00874] The compound of any one of paragraphs [00866]-[00869], wherein E1 is the pharmacophore; and E2 is the first chemical moiety, wherein the first chemical moiety is OH, OMe, NΉ2, a probe, a metal chelator, or an imaging agent.
[00875] The compound of any one of paragraphs [00860]-[00874], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00876] The compound of paragraph [00875], wherein the Huntington’s disease phenotype is associated with a non- wild-type HTT gene that differs from a wild type HTT gene in a repeat expansion mutation.
[00877] The compound of any one of paragraphs [00860]-[00876], wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
[00878] The compound of any one of paragraphs [00860]-[00876], wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CTG)Z (SEQ ED NO: 182), wherein z is an integer from 1-100.
[00879] The compound of any one of paragraphs [00860]-[00878], wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
[00880] The compound of any one of paragraphs [00860]-[00879], wherein the pharmacophore is a peptide nucleic acid.
[00881] The compound of paragraph [00860], wherein the compound is:
Figure imgf000166_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[00882] The compound of paragraph [00881], wherein N-terminus is acyl.
[00883] The compound of paragraph [00881], wherein N-terminus is acetyl.
[00884] The compound of paragraph [00881], wherein N-terminus is H.
[00885] The compound of any one of paragraphs [00881]-[00884], wherein C-Terminus is NTh. [00886] The compound of any one of paragraphs [00881]-[00885], wherein L3 is absent.
[00887] The compound of any one of paragraphs [00881]-[00885], wherein L3 is - NH(CH2CH20)2CH2C(0)-, -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-, - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-, or -NH(CH2)5C(0)-.
[00888] The compound of any one of paragraphs [00881]-[00885], wherein L3 is - NH(CH2CH20)2CH2C(0)-.
[00889] The compound of any one of paragraphs [00881]-[00885], wherein L3 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00890] The compound of any one of paragraphs [00881]-[00889], wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
[00891] The compound of paragraph [00860], wherein the compound is:
Figure imgf000168_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L4 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[00892] The compound of paragraph [00891], wherein JV-Terminus is H.
[00893] The compound of paragraph [00891], wherein C-Terminus is MB.
[00894] The compound of any one of paragraphs [00891]-[00893], wherein L4 is absent.
[00895] The compound of any one of paragraphs [00891]-[00893], wherein L4 is - NH(CH2CH20)2CH2C(0)-, -NH(CH2CH20)2CH2C(0)-Mi(CH2CH20)2CH2C(0)-, - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(Mi2)C(0)-, or -NH(CH2)5C(0)-.
[00896] The compound of any one of paragraphs [00891]-[00893], wherein L4 is - NH(CH2CH20)2CH2C(0)-.
[00897] The compound of any one of paragraphs [00891]-[00893], wherein L4 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00898] The compound of any one of paragraphs [00891]-[00897], wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
[00899] A compound comprising a structure that is: N-Terminus - L 1 — PEP 1— L 2 — SOL 1— L 3-PNA 1-£-
Figure imgf000169_0001
wherein: the number of units with variables defined independently is at least 11;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or ME;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a gene associated with a neurodegenerative disease phenotype.
[00900] The compound of paragraph [00899], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17.
[00901] The compound of paragraph [00899], wherein the number of units with variables defined independently is 14. [00902] The compound of any one of paragraphs [00899]-[00901], wherein A/-Terminus is H and C-Terminus is ME
[00903] The compound of any one of paragraphs [00899]-[00901], wherein jV-Terminus is acyl and C-Terminus is NH2.
[00904] The compound of any one of paragraphs [00899]-[00901], wherein iV-Terminus is acetyl and C-Terminus is NH2.
[00905] The compound of any one of paragraphs [00899]-[00904], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[00906] The compound of any one of paragraphs [00899]-[00904], wherein at least one iteration of R1 is hydroxylmethyl.
[00907] The compound of any one of paragraphs [00899]-[00904], wherein at least half the iterations of R1 are hydroxylmethyl and the other iterations of R1 are H.
[00908] The compound of any one of paragraphs [00899]-[00907], wherein each of L1, L2, L3, L4, L5, and L6 is absent.
[00909] The compound of any one of paragraphs [00899]-[00908], wherein PEP1 and PEP2 are absent.
[00910] The compound of any one of paragraphs [00899]-[00908], wherein one of PEP 1 and PEP2 is a peptide sequence that is a nuclear localization sequence and the other is absent. [00911] The compound of any one of paragraphs [00899]-[00908], wherein SOL1 is the water- solubilizing group and SOL2 is absent.
[00912] The compound of any one of paragraphs [00899]-[00908], wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP2, and SOL2 is absent, and SOL1 is the water-solubilizing group.
[00913] The compound of any one of paragraphs [00899]-[00912], wherein the water- solubilizing group is a group that contains multiple positive charges at physiological pH.
[00914] The compound of any one of paragraphs [00899]-[00912], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000170_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group; R4a is H, alkyl, or a nitrogen atom protecting group; R5a is alkyl or O-alkyl, any of which is unsubstituted or substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-100.
[00915] The compound of paragraph [00914], wherein p is 5, 6, 7, or 8.
[00916] The compound of paragraph [00914], wherein p is 7.
[00917] The compound of any one of paragraphs [00899]-[00912], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000171_0001
wherein p is an integer that is 5, 6, 7, or 8.
[00918] The compound of any one of paragraphs [00899]-[00912], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000171_0002
wherein p is an integer that is 5, 6, 7, or 8.
[00919] The compound of paragraph [00917] or paragraph [00918], wherein p is 7.
[00920] The compound of any one of paragraphs [00899]-[00919], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[00921] The compound of any one of paragraphs [00899]-[00920], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000171_0003
[00922] The compound of any one of paragraphs [00899]-[00921], wherein each R2 group in the structure is independently:
Figure imgf000172_0001
[00923] The compound of any one of paragraphs [00899]-[00920], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000172_0002
[00924] The compound of any one of paragraphs [00899]-[00920] and [00923], wherein each R2 group in the structure is independently:
Figure imgf000172_0003
[00925] The compound of any one of paragraphs [00899]-[00922], wherein the heterocycles of the R2 groups form a sequence that repeats at least twice, wherein the sequence is, from N- Terminus to C-Terminus:
Figure imgf000172_0004
[00926] The compound of any one of paragraphs [00899]-[00920], [00923], and [00924], wherein the heterocycles of the R2 groups form a sequence that repeats at least twice, wherein the sequence is, from N -Terminus to C-Terminus:
Figure imgf000173_0001
[00927] The compound of any one of paragraphs [00899]-[00922] and [00925], wherein the compound binds to a mRNA sequence transcribed from the gene associated with the neurodegenerative disease phenotype.
[00928] The compound of any one of paragraphs [00899]-[00922] and [00925], wherein the compound binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
[00929] The compound of any one of paragraphs [00899]-[00922] and [00925], wherein the compound binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of a HTT gene.
[00930] The compound of any one of paragraphs [00899]-[00920], [00923], [00924], and [00926], wherein the compound binds to a DNA sequence of the gene associated with the neurodegenerative disease phenotype.
[00931] The compound of any one of paragraphs [00899]-[00920], [00923], [00924], and [00926], wherein the compound binds to a DNA sequence of a gene associated with a Huntington’s disease phenotype.
[00932] The compound of any one of paragraphs [00899]-[00920], [00923], [00924], and [00926], wherein the compound binds to a DNA sequence of a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of a HTT gene.
[00933] The compound of paragraph [00929] or paragraph [00932], wherein the HTT gene is a non-wild type HTT gene.
[00934] The compound of paragraph [00933], wherein the non-wild type HTT gene differs from a wild type HTT gene in a repeat expansion mutation.
[00935] The compound of any one of paragraphs [00899]-[00922] and [00925], wherein the compound binds to a mRNA sequence of (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
[00936] The compound of paragraph [00899], wherein the compound is:
Figure imgf000174_0001
or a pharmaceutically-acceptable salt or ionized form thereof. [00937] The compound of paragraph [00899], wherein the compound is:
Figure imgf000174_0002
or a pharmaceutically-acceptable salt or ionized form thereof.
[00938] A compound comprising an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000175_0001
wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[00939] The compound of paragraph [00938], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[00940] The compound of paragraph [00938] or paragraph [00939], wherein R5 is linear alkyl. [00941] The compound of paragraph [00938] or paragraph [00939], wherein R5 is methyl. [00942] The compound of any one of paragraphs [00938]-[00941], wherein n is 3.
[00943] The compound of any one of paragraphs [00938]-[00941], wherein n is 4.
[00944] The compound of any one of paragraphs [00938]-[00943], wherein p is 6.
[00945] The compound of any one of paragraphs [00938]-[00943], wherein p is 7.
[00946] The compound of any one of paragraphs [00938]-[00943], wherein p is 8.
[00947] The compound of paragraph [00938], further comprising a pharmacophore attached to the oligomeric structure, wherein the oligomeric structure, wherein the first chemical moiety, and the second chemical moiety form:
Figure imgf000176_0001
, wherein:
E1 is the pharmacophore, and p is an integer that is 1-100.
[00948] The compound of paragraph [00947], wherein p is 6.
[00949] The compound of paragraph [00947], wherein p is 7.
[00950] The compound of paragraph [00947], wherein p is 8.
[00951] The compound of any one of paragraphs [00947]-[00950], wherein the pharmacophore interferes with expression of a gene associated with a neurodegenerative disease phenotype. [00952] The compound of paragraph [00951], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00953] The compound of paragraph [00952], wherein the Huntington’s disease phenotype is associated with a non- wild-type HTT gene that differs from a wild type HTT gene in a repeat expansion mutation.
[00954] The compound of any one of paragraphs [00947]-[00953], wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
[00955] The compound of any one of paragraphs [00947]-[00953], wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1-100.
[00956] The compound of any one of paragraphs [00947]-[00955], wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
[00957] The compound of any one of paragraphs [00947]-[00955], wherein the pharmacophore is a peptide nucleic acid.
[00958] The compound of paragraph [00947], wherein the compound is:
Figure imgf000177_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[00959] The compound of paragraph [00958], wherein L3 is absent.
[00960] The compound of paragraph [00958] or paragraph [00959], wherein each instance of
Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen. [00961] The compound of paragraph [00958], wherein the compound is:
Figure imgf000177_0002
or a pharmaceutically-acceptable salt or ionized form thereof.
[00962] A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any one of paragraphs [00938]-[00926],
[00963] The method of paragraph [00962], wherein the condition is the neurodegenerative disease.
[00964] The method of paragraph [00962] or paragraph [00963], wherein the condition is associated with a gene having a repeat expansion mutation. [00965] The method of any one of paragraphs [00962]-[00964], wherein the condition is Huntington’s disease.
[00966] The method of any one of paragraphs [00962]-[00965], wherein the subject is human. [00967] A compound comprising:
1) a pharmacophore that binds to a nucleic acid sequence that contains a subsequence that is (CAG)z, wherein z is an integer from 1-100 (SEQ ID NO: 135); and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000178_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
[00968] The compound of paragraph [00967], wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
[00969] The compound of paragraph [00967] or paragraph [00968], wherein R5 is linear alkyl. [00970] The compound of paragraph [00967] or paragraph [00968], wherein R5 is methyl. [00971] The compound of any one of paragraphs [00967]-[00970], wherein n is 3.
[00972] The compound of any one of paragraphs [00967]-[00970], wherein n is 4.
[00973] The compound of paragraph [00967], further comprising a first chemical moiety attached to the oligomeric structure, wherein the oligomeric structure, the first chemical moiety, and the pharmacophore form:
Figure imgf000179_0001
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; and p is an integer that is 1-100.
[00974] The compound of paragraph [00973], wherein p is 6.
[00975] The compound of paragraph [00973], wherein p is 7.
[00976] The compound of paragraph [00973], wherein p is 8.
[00977] The compound of any one of paragraphs [00973]-[00976], wherein E1 is the first chemical moiety, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a probe, a metal chelator, or an imaging agent; and E2 is the pharmacophore.
[00978] The compound of any one of paragraphs [00973]-[00977], wherein E1 is an acyl group, and E2 is the pharmacophore.
[00979] The compound of any one of paragraphs [00973]-[00977], wherein E1 is acetyl, E2 is the pharmacophore.
[00980] The compound of any one of paragraphs [00973]-[00977], wherein E1 is hydrogen and E2 is the pharmacophore.
[00981] The compound of any one of paragraphs [00973]-[00976], wherein E1 is the pharmacophore; and E2 is the first chemical moiety, wherein the first chemical moiety is OH, OMe, M¾, a probe, a metal chelator, or an imaging agent.
[00982] The compound of any one of paragraphs [00967]-[00981], wherein the subsequence that is (CAG)z is a mRNA sequence transcribed from the gene associated with a neurodegenerative disease phenotype.
[00983] The compound of paragraph [00982], wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
[00984] The compound of paragraph [00983], wherein the Huntington’s disease phenotype is associated with a non-wild-type HTT gene that differs from a wild type HTT gene in a repeat expansion mutation.
[00985] The compound of any one of paragraphs [00967]-[00984], wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
[00986] The compound of any one of paragraphs [00967]-[00985], wherein the pharmacophore is a peptide nucleic acid.
[00987] The compound of paragraph [00967], wherein the compound is:
Figure imgf000180_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[00988] The compound of paragraph [00987], wherein N-terminus is acyl.
[00989] The compound of paragraph [00987], wherein N-terminus is acetyl.
[00990] The compound of paragraph [00987], wherein N-terminus is H.
[00991] The compound of any one of paragraphs [00987]-[00990], wherein C-Terminus is MB. [00992] The compound of any one of paragraphs [00987]-[00991], wherein L3 is absent.
[00993] The compound of any one of paragraphs [00987]-[00991], wherein L3 is - NH(CH2CH20)2CH2C(0)-, -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-, - NHCH(C00H)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-, or -NH(CH2)5C(0)-.
[00994] The compound of any one of paragraphs [00987]-[00991], wherein L3 is - NH(CH2CH20)2CH2C(0)-. [00995] The compound of any one of paragraphs [00987]-[00991], wherein L3 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[00996] The compound of any one of paragraphs [00987]-[00995], wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
[00997] The compound of paragraph [00967], wherein the compound is:
Figure imgf000181_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L4 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
[00998] The compound of paragraph [00997], wherein JV-Terminus is H.
[00999] The compound of paragraph [00997], wherein C-Terminus is NH2.
[001000] The compound of any one of paragraphs [00997]-[00999], wherein L4 is absent. [001001] The compound of any one of paragraphs [00997]-[00999], wherein L4 is - NH(CH2CH2O)2CH2C(O)-, -NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-, - NHCH(COOH)C(CH3)2S-SC(CH3)2CH(NH2)C(0)-, or -NH(CH2)5C(0)-.
[001002] The compound of any one of paragraphs [00997]-[00999], wherein L4 is - NH(CH2CH20)2CH2C(0)-. [001003] The compound of any one of paragraphs [00997]-[00999], wherein L4 is - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-.
[001004] The compound of any one of paragraphs [00997]-[001003], wherein each instance of
Q\ Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen. [001005] A compound comprising a structure that is:
Figure imgf000182_0001
wherein: the number of units with variables defined independently is at least 11;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound binds to a nucleic acid sequence that contains a subsequence that is (CAG)z, wherein z is an integer from 1-100.
[001006] The compound of paragraph [001005], wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17.
[001007] The compound of paragraph [001005], wherein the number of units with variables defined independently is 14.
[001008] The compound of any one of paragraphs [001005]-[001007], wherein N -Terminus is H and C-Terminus is NH2.
[001009] The compound of any one of paragraphs [001005]-[001007], wherein N -Terminus is acyl and C-Terminus is NH2.
[001010] The compound of any one of paragraphs [001005]-[001007], wherein N -Terminus is acetyl and C-Terminus is NH2.
[001011] The compound of any one of paragraphs [001005]-[001010], wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
[001012] The compound of any one of paragraphs [001005]-[001010], wherein at least one iteration of R1 is hydroxylmethyl.
[001013] The compound of any one of paragraphs [001005]-[001010], wherein at least half the iterations of R1 are hydroxylmethyl and the other iterations of R1 are H.
[001014] The compound of any one of paragraphs [001005]-[001013], wherein each of L1, L2, L3, L4, L5, and L6 is absent.
[001015] The compound of any one of paragraphs [001005]-[001014], wherein PEP1 and PEP2 are absent.
[001016] The compound of any one of paragraphs [001005]-[001014], wherein one of PEP1 and PEP2 is a peptide sequence that is a nuclear localization sequence and the other is absent. [001017] The compound of any one of paragraphs [001005]-[001014], wherein SOL1 is the water-solubilizing group and SOL2 is absent.
[001018] The compound of any one of paragraphs [001005]-[001014], wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP2, and SOL2 is absent, and SOL1 is the water-solubilizing group. [001019] The compound of any one of paragraphs [001005]-[001018], wherein the water- solubilizing group is a group that contains multiple positive charges at physiological pH. [001020] The compound of any one of paragraphs [001005]-[001018], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000184_0001
, wherein
R a is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is alkyl or O-alkyl, any of which is unsubstituted or substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-100.
[001021] The compound of paragraph [001020], wherein p is 5, 6, 7, or 8.
[001022] The compound of paragraph [001020], wherein p is 7.
[001023] The compound of any one of paragraphs [001005]-[001018], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000184_0002
wherein p is an integer that is 5, 6, 7, or 8.
[001024] The compound of any one of paragraphs [001005]-[001018], wherein the water- solubilizing group of SOL1 is a group of formula:
Figure imgf000184_0003
wherein p is an integer that is 5, 6, 7, or 8.
[001025] The compound of paragraph [001023] or paragraph [001024], wherein p is 7.
[001026] The compound of any one of paragraphs [001005]-[001025], wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
[001027] The compound of any one of paragraphs [001005]-[001026], wherein the heterocycles of the R2 groups are each independently:
Figure imgf000185_0001
[001028] The compound of any one of paragraphs [001005]-[001027], wherein each R2 group in the structure is independently:
Figure imgf000185_0002
[001029] The compound of any one of paragraphs [001005]-[001028], wherein the heterocycles of the R2 groups form a sequence that repeats at least twice, wherein the sequence is, from N- Terminus to C-Terminus:
Figure imgf000185_0003
[001030] The compound of any one of paragraphs [001005]-[001029], wherein the subsequence that is (CAG)z is a mRNA sequence transcribed from the gene associated with a neurodegenerative disease phenotype.
[001031] The compound of any one of paragraphs [001005]-[001029], wherein the subsequence that is (CAG)z is a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
[001032] The compound of any one of paragraphs [001005]-[001029], wherein the subsequence that is (CAG)z is a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype, and the compound binds to the mRNA sequence by interactions between the heterocycles of the R2 groups and nucleobases of a HTT gene.
[001033] The compound of paragraph [001032], wherein the HTT gene is a non-wild type HTT gene.
[001034] The compound of paragraph [001033], wherein the non-wild type HTT gene differs from a wild type HTT gene in a repeat expansion mutation.
[001035] The compound of paragraph [001005], wherein the compound is:
Figure imgf000186_0001
pharmaceutically-acceptable salt or ionized form thereof.
[001036] A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any one of paragraphs [00967]-[00981] and [00987]-[001029].
[001037] The method of paragraph [001036], wherein the condition is a neurodegenerative disease.
[001038] The method of paragraph [001036] or paragraph [001037], wherein the condition is associated with a gene having a repeat expansion mutation.
[001039] The method of any one of paragraphs [001036]-[001038], wherein the condition is Huntington’s disease.
[001040] The method of any one of paragraphs [001036]-[001039], wherein the subject is human. EXAMPLES
EXAMPLE 1: Targeting HTT mRNA transcripts with Compound 76 decreased production of mutant HTT.
[001041] Mutant Huntingtin protein (mHTT) and wild type Huntingtin protein (wtHTT) knockdown in the brain were assessed using Compound 76. Adult zQ175KI heterozygous mice with 190 CAG repeat length in exon 1 of HTT were injected subcutaneously with 60 mg/kg body weight per injection of Compound 76 (N=4) or equivalent volume of PBS (N=3). Mice were injected on days 1 and 4, and tissues collected on day 7. Mouse brain hemispheres were snap frozen in liquid nitrogen immediately after euthanizing each mouse. After collection, brain hemispheres were lysed and protein was isolated for immunoblotting with fluorescence quantification of wtHTT and mHTT bands. For lysate preparation, the samples were thawed on ice. Next, 800 pi of homogenization buffer (lxPBS mix with Protease Inhibitor Cocktail Set III, EDTA-Free (Millipore, cat# 539134) (1:200) and phosphatase inhibitor cocktail 2 (Millipore cat #524625)(1 : 100) was added to each sample, followed by homogenization on ice using a prechilled polytetrafluoroethylene (PTFE) tissue homogenizer. An aliquot of tissue homogenate was used to measure protein concentration using Bicinchoninic Acid assay (BCA assay, Sigma). Next, 300 μg samples of homogenate were placed into tubes containing cold RIPA buffer (Millipore, cat# 20-188) supplied with proteinase inhibitor III (1 :200) and phosphatase inhibitor 2 (1 : 100) to a final protein concentration of less than 5 mg/ml. Samples were incubated on ice for 30 min and then centrifuge at 14,000 rpm for 20 min at 4 °C. Supernatants were recovered and protein concentration re-measured.
[001042] For SDS-PAGE, 15 μg samples in IX reducing Laemmli sample buffer (Bio-Rad, cat# 1610747) were loaded on 4-12% gradient gels (Bolt™ 4-12% Bis-Tris Plus, Invitrogen, cat# NW04122BOX) with MES Running buffer and run for 1 hour on ice at 165 V. Then, gels were transferred on PVDF-FL membrane (Millipore cat# IPFL00005) using Tris-Glycine transferring buffer supplied with 10% methanol. Gels were transferred overnight in the cold room (4 °C) at 30V. Next day, the membranes were blocked for 1 hour at RT using SEA BLOCK Blocking Buffer (Therm oFisher, cat# 37527) and probed for mutant HTT using anti -Huntingtin antibody (EPR5526, rabbit monoclonal 1:5000 dilution, Abeam, cat# AB 109115) or anti-PolyQ expansion antibody, clone 5TF1-1C2 (Millipore, mouse monoclonal 1:5000 cat# MAB1574) and anti-beta-actin antibody (mouse monoclonal 1 : 10000, Sigma, cat# A5441), which were used as loading control for each lane. Membranes were incubated overnight at 4 °C. Next day, the membranes were washed with PBS Tween 0.05% (PBST) twice and incubated with secondary antibodies from Li-Cor, goat anti-rabbit 800 (IRDye800CW) and goat anti-mouse 680 (RDye680CW) at 1 : 30000 dilution. After incubation for 1 hour at room temperature, membranes were washed 3 times with PBST and scanned on Li-Cor imager to get fluorescent intensities for Huntingtin (HTT), mutant Huntingtin (mHTT), and beta-actin. Quantification was performed using Li-Cor Image Studio™ Mutant HTT and wild-type HTT quantities were normalized for loading using beta-actin and expressed relative to PBS-treated control. Statistical analysis was performed using a 2-tailed Students two-sample T-test assuming equal variances with 2-tailed analysis.
[001043] FIG. 1, Panel A illustrates expression relative to the average PBS treated control value for each protein (wtHTT or mHTT) after normalizing to beta-actin for loading control. The PBS group had three mice and the Compound 76 group had four. Data were analyzed by comparing Compound 76 treated to PBS treated using T-test for two samples with equal variances (two-tailed p=0.02. NS (non-significant) two-tailed p>0.05). FIG. 1, Panel B illustrates a schematic of transcription engagement by PNA binding to mutant HTT mRNA. These results showed that Compound 76 knocked down mutant HTT expression in the brain of treated mice. Subcutaneous dosing of Compound 76 resulted in a statistically significant decreased production of mutant HTT relative to wild-type HTT as compared with PBS-treated controls. Compound 76 crosses the BBB to target HTT mRNA transcripts, thereby knocking down mutant HTT in the mouse brain.
EXAMPLE 2: Targeting the HTT gene transcribed DNA with Compound 77 decreased production of mutant HTT.
[001044] mHTT and wtHTT knockdown in the brain were assessed using Compound 77. Adult zQ175KI heterozygous mice with 190 CAG repeat length in exon 1 of HTT were injected subcutaneously with 30 mg/kg body weight per injection of Compound 77 (N=3) or equivalent volume of PBS (N=3). Mice were injected on days 1 and 4, and tissues collected on day 7. Mouse brain hemispheres were snap frozen in liquid nitrogen immediately after euthanizing each mouse. After collection, brain hemispheres were lysed and protein isolated for immunoblotting with fluorescence quantification of wtHTT and mHTT bands. For lysate preparation, the samples were thawed on ice. Next, 800 mΐ of homogenization buffer (lxPBS mix with Protease Inhibitor Cocktail Set III, EDTA-Free (Millipore, cat# 539134) (1 :200) and phosphatase inhibitor cocktail 2 (Millipore cat #524625)(1:100) was added to each sample, followed by homogenization on ice using a prechilled PTFE tissue homogenizer. An aliquot of tissue homogenate was used to measure protein concentration using Bicinchoninic Acid assay (BCA assay, Sigma). Next, 300 μg samples of homogenate were placed into tubes containing cold RIPA buffer (Millipore, cat# 20-188) supplied with proteinase inhibitor III (1 :200) and phosphatase inhibitor 2 (1:100) to a final protein concentration of less than 5 mg/ml. Samples were incubated on ice for 30 min and then spun by centrifuge at 14,000 rpm for 20 min at 4 °C. Supernatants were recovered and protein concentration re-measured.
[001045] For SDS-PAGE, 15 μg samples in IX reducing Laemmli sample buffer (Bio-Red, cat# 1610747) were loaded on 4-12% gradient gels (Bolt™ 4-12% Bis-Tris Plus, Invitrogen, cat# NW04122BOX) with MES Running buffer and run for 1 hour on ice at 165 V. Then, gels were transferred on PVDF-FL membrane (Millipore cat# IPFL00005) using Tris-Glycin transferring buffer supplied with 10% methanol. Gels were transferred overnight in the cold room (4 °C) at 30V. Next day, the membranes were blocked for 1 hour at RT using SEA BLOCK Blocking Buffer (Therm oFisher, cat# 37527) and probed for mutant HTT using anti-Huntingtin antibody (EPR5526, rabbit monoclonal 1:5000 dilution, Abeam, cat# AB 109115) or anti-PolyQ expansion antibody, clone 5TF1-1C2 (Millipore, mouse monoclonal 1:5000 cat# MAB1574) and anti- beta-actin antibody (mouse monoclonal 1:10000, Sigma, cat# A5441) which was were used as loading control for each lane. Membranes were incubated overnight at 4 °C. Next day, the membranes were washed with PBS Tween 0.05% (TBST) twice and incubated with secondary antibodies from Li-Cor, goat anti-rabbit 800 (IRDye800CW) and goat anti-mouse 680 (RDye680CW) at 1 : 30000 dilution. After incubation for 1 hour at room temperature, membranes were washed 3 times with PBST and scanned on Li-Cor imager to get fluorescent intensities for Huntingtin (HTT), mutant Huntingtin (mHTT) and beta-actin. Quantification was performed using Li-Cor Image Studio™. Mutant HTT and wild-type HTT quantities were normalized for loading using beta-actin and expressed relative to PBS-treated control. Statistical analysis was performed using a 2-tailed Students two-sample T-test assuming equal variances with 2-tailed analysis.
[001046] FIG. 2, Panel A illustrates expression relative to the average PBS treated control value for each protein (wtHTT or mHTT) after normalizing to wtHTT. There were 3 mice in the PBS group and 4 mice in the Compound 77 group. Data were analyzed by comparing wtHTT to mHTT in the treatment group using T-test for two samples with equal variances (two-tailed p<0.05). FIG. 2, Panel B illustrates a schematic of genome engagement by PNA binding to mutant HTT DNA. Subcutaneous dosing of Compound 77 resulted in a statistically significant decreased production of mutant HTT relative to wild-type HTT as compared with PBS-treated controls. Compound 77 crosses the BBB to target the HTT gene transcribed DNA, thereby knocking down mutant HTT in the mouse brain.
EXAMPLE 3: Western blot analysis of HTT protein knockdown in in human GM09197 fibroblasts treated selected compounds of the disclosure
[001047] Cells from patient-derived fibroblast cell line GM09197 (Coriell Institute for Medical Research, Camden, NJ), were plated in 24-well plates at 50,000 cells/well and treated with PNA compounds at the indicated concentration in TABLE 8 for 3 days. Cells were maintained at 37 °C and 5% CO2 in MEM with non-essential amino acids (Coming Inc., Corning, NY, cat. n# 10- 009-CV) supplemented with 15% heat inactivated FBS (Corning Inc., Corning, NY cat. n# 35- 016-CV).
[001048] After 3 days of treatment, cells were harvested with a trypsin-EDTA solution 0.25% (Invitrogen, Carlsbad, CA, cat. n# 25200072) and lysed using M-Per buffer (Thermo Fischer Scientific, Waltham, MA, cat. n# 78503) following the company direction. Protein extracts were quantified using BCA assay (Pierce BCA protein Assay Kit cat. n# 23225, Thermo Fischer Scientific, Waltham, MA). SDS-PAGE 3-8% gradient gels with Tris Acetate Running Buffer 0.1% SDS (Invitrogen) were used to separate mutant HTT from wild type HTT proteins. Gels were mn at 150V for 2.5 hours. After gel electrophoresis, proteins were transferred to a nitrocellulose membrane and western blot was performed using primary antibodies specific for HTT (1:4000, Abeam, cat. n# abl09115) and vinculin (1:4000, Cell Signaling, cat n# 13901S). HRP conjugate anti-rabbit secondary antibody (1:10,000, Jackson ImmunoResearch Laboratories, cat. n# 111-035-045) was used for visualizing proteins using SuperSignal™ West Pico Plus Chemiluminescent Substrate (Thermo Fischer Scientific). Protein bands were quantified using iBright Analysis Software (Thermo Fischer Scientific). Bands were normalized according to vinculin expression and the HTT expression inhibition was calculated as a relative value to untreated control cells. Observed percent knockdown of wildtype HTT (wt HTT) and mutant HTT (mut HTT) is provided in TABLE 8.
TABLE 8
Figure imgf000190_0001
N.T.: Not tested.
EXAMPLE 4: Synthesis and purification of Compounds of the disclosure [001049] Synthesis of crude PNA: PNA synthesis was performed using Fmoc solid-phase peptide chemistry on an Intavis MultiPep RSi (25 pmol scale) at ambient temperature. TentaGel® R RAM resin (0.18 meq/g) was swelled in N,N-dimethylformamide (DMF) (1 mL, 3 x 10 min). Fmoc groups were deprotected with 20% piperidine (v/v) in DMF (0.8 mL, 2 x 10 minutes). Following deprotection, the resin was washed with DMF (6 x 1 mL) and the next PNA residue was coupled to the N-terminus of resin-bound PNA upon treatment with a mixture of Fmoc-protected monomer (85 pmol, 3.4x, 0.2 M in NMP), HATU (80 pmol, 3.2x, 0.5 M in DMF), and N,N-diisopropylethylamine (DIPEA, 83 pmol, 3.3x, 0.52 M in DMF) (double coupling: 2 min pre-activation and 30 min coupling). After coupling, the resin was acetyl capped with 5% acetic anhydride and 6% 2,6-lutidine (v/v) in DMF (5 min), and subsequently washed with DMF (6 x 1 mL). Upon completion of all synthetic cycles, the resin was washed with DMF (5x) and DCM (5x). PNA was simultaneously cleaved and deprotected upon treatment with a mixture of trifluoroacetic acid/triflic acid/thioanisol/m-cresol (5 mL, 6:2: 1:1) under agitation for 90 minutes. PNA was precipitated in ice-cold diethyl ether (45 mL), centrifuged, isolated from the supernatant, washed with ice-cold diethyl ether (50 mL), and dried under vacuum.
[001050] Purification of PNA: Crude PNA was dissolved in Milli-Q water (5 mL) and filtered through a nylon syringe-tip filter (0.45 pm pore size). Preparative reversed-phase high-pressure liquid chromatography (RP-HPLC) was performed on a Dionex Ultimate™ 3000 equipped with a Flypersil GOLD™ C18aq 30 x 250 mm column, with a 5 pm particle size and 175 A pore size. A 30-minute linear gradient of acetonitrile (5-25%) in water with 0.1% TFA was used as the mobile phase. HPLC eluate was fractionated based on UV absorbance (l = 254 nm) and fractional purity was assessed via MALDI-TOF in linear positive mode with a matrix of CF1CA. Pure fractions were lyophilized, dissolved in water, combined, and re-lyophilized. Pure PNA was dissolved in PBS and the concentration of the PNA solution was determined via absorbance spectroscopy (e (l = 260 nm) = 148,300 cm'1 M'1). Selected compounds were characterized by matrix-assisted laser desorption/ionization mass spectroscopy (MALDI-MS) or ESI+MS. Observed masses of selected compounds are presented in TABLE 9.
TABLE 9
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
[001051] While preferred embodiments of the present invention have been shown and/or described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:
1. A compound compri sing :
1) a pharmacophore that interferes with expression of a gene associated with a neurodegenerative disease phenotype; and
2) connected to the pharmacophore, an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000195_0001
ionized form thereof, wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
2. The compound of claim 1, wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or
N(PgN).
3. The compound of claim 1 or claim 2, wherein R5 is linear alkyl.
4. The compound of claim 1 or claim 2, wherein R5 is methyl.
5. The compound of any one of claims 1-4, wherein n is 3.
6. The compound of any one of claims 1-4, wherein n is 4.
7. The compound of claim 1, further comprising a first chemical moiety attached to the oligomeric structure, wherein the oligomeric structure, the first chemical moiety, and the pharmacophore form:
Figure imgf000196_0001
E1 is the first chemical moiety, and E2 is the pharmacophore; or E1 is the pharmacophore, and E2 is the first chemical moiety; and p is an integer that is 1-100.
8. The compound of claim 7, wherein p is 6.
9. The compound of claim 7, wherein p is 7.
10. The compound of claim 7, wherein p is 8.
11. The compound of any one of claims 7-10, wherein E1 is the first chemical moiety, wherein the first chemical moiety is hydrogen, acyl, a group that together with the nitrogen atom to which E1 is bound forms a carbamate, a probe, a metal chelator, or an imaging agent; and E2 is the pharmacophore.
12. The compound of any one of claims 7-11, wherein E1 is an acyl group, and E2 is the pharmacophore.
13. The compound of any one of claims 7-11, wherein E1 is acetyl, E2 is the pharmacophore.
14. The compound of any one of claims 7-11, wherein E1 is hydrogen and E2 is the pharmacophore.
15. The compound of any one of claims 7-10, wherein E1 is the pharmacophore; and E2 is the first chemical moiety, wherein the first chemical moiety is OH, OMe, ME, a probe, a metal chelator, or an imaging agent.
16. The compound of any one of claims 1-15, wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
17. The compound of claim 16, wherein the Huntington’s disease phenotype is associated with a non-wild-type HTT gene that differs from a wild type HTT gene in a repeat expansion mutation.
18. The compound of any one of claims 1-17, wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
19. The compound of any one of claims 1-17, wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1- 100
20. The compound of any one of claims 1-19, wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
21. The compound of any one of claims 1-20, wherein the pharmacophore is a peptide nucleic acid.
22. The compound of claim 1, wherein the compound is:
Figure imgf000197_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
23. The compound of claim 22, wherein N-terminus is acyl.
24. The compound of claim 22, wherein N-terminus is acetyl.
25. The compound of claim 22, wherein N-terminus is H.
26. The compound of any one of claims 22-25, wherein C-Terminus is NTh
27. The compound of any one of claims 22-26, wherein L3 is absent.
28. The compound of any one of claims 22-26, wherein L3 is -NH(CH2CH20)2CH2C(0)-, - NH(CH2CH20)2CH2C(0)-NH(CH2CH20)2CH2C(0)-, -NHCH(COOH)C(CH3)2S- SC(CH3)2CH(NH2)C(0)-, or -NH(CH2)5C(0)-.
29. The compound of any one of claims 22-26, wherein L3 is -NH(CH2CH20)2CH2C(0)-.
30. The compound of any one of claims 22-26, wherein L3 is -NH(CH2CH20)2CH2C(0)- NH(CH2CH20)2CH2C(0)-.
31. The compound of any one of claims 22-30, wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
32. The compound of claim 1, wherein the compound is:
Figure imgf000199_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L4 is a linker group or absent; N -Terminus is H, acyl, a group that together with the nitrogen atom to which the N -Terminus is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
33. The compound of claim 32, wherein N -Terminus is H.
34. The compound of claim 32, wherein C-Terminus is NH2.
35. The compound of any one of claims 32-34, wherein L4 is absent.
36. The compound of any one of claims 32-34, wherein L4 is -NH(CH2CH2O)2CH2C(O)-, -
NH(CH2CH2O)2CH2C(0)-NH(CH2CH2O)2CH2C(0)-, -NHCH(COOH)C(CH3)2S-
SC(CH3)2CH(NH2)C(0)-, or -NH(CH2)5C(0)-.
37. The compound of any one of claims 32-34, wherein L4 is -NH(CH2CH2O)2CH2C(O).
38. The compound of any one of claims 32-34, wherein L4 is -NH(CH2CH2O)2CH2C(O) NH(CH2CH20)2CH2C(0)-.
39. The compound of any one of claims 32-38, wherein each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
40. A compound comprising a structure that is:
Figure imgf000200_0001
wherein: the number of units with variables defined independently is at least 11;
A-Terminus is H, acyl, a group that together with the nitrogen atom to which the A-Terminus is bound forms a carbamate, a probe, a metal chelator, or a biological agent; each R1 is independently alkyl that is unsubstituted or substituted or H, wherein at least one iteration of R1 is a hydroxyalkyl group; each Ralpha is independently alkyl that is unsubstituted or substituted or H; each R2 is independently methyl substituted with a heterocycle;
C-Terminus is OH, O-alkyl, a peptide sequence, or NH2;
PEP1 is a peptide sequence or absent;
PEP2 is a peptide sequence or absent;
SOL1 is a water-solubilizing group or absent;
SOL2 is a water-solubilizing group or absent;
PNA1 is a peptide nucleic acid sequence or absent;
PNA2 is a peptide nucleic acid sequence or absent; L1 is a linker group or absent;
L2 is a linker group or absent;
L3 is a linker group or absent;
L4 is a linker group or absent;
L5 is a linker group or absent; and L6 is a linker group or absent, or a pharmaceutically-acceptable salt or ionized form thereof, wherein the compound interferes with expression of a gene associated with a neurodegenerative disease phenotype.
41. The compound of claim 40, wherein the number of units with variables defined independently is 11, 12, 13, 14, 15, 16, or 17.
42. The compound of claim 40, wherein the number of units with variables defined independently is 14.
43. The compound of any one of claims 40-42, wherein N -Terminus is H and C-Terminus is NH2.
44. The compound of any one of claims 40-42, wherein N -Terminus is acyl and C-Terminus is NH2.
45. The compound of any one of claims 40-42, wherein N -Terminus is acetyl and C-Terminus is NH2.
46. The compound of any one of claims 40-45, wherein each R1 is independently H, hydroxylmethyl, or 4-guanidinobut-l-yl.
47. The compound of any one of claims 40-45, wherein at least one iteration of R1 is hydroxylmethyl.
48. The compound of any one of claims 40-45, wherein at least half the iterations of R1 are hydroxylmethyl and the other iterations of R1 are H.
49. The compound of any one of claims 40-48, wherein each of L1, L2, L3, L4, L5, and L6 is absent.
50. The compound of any one of claims 40-49, wherein PEP1 and PEP2 are absent.
51. The compound of any one of claims 40-49, wherein one of PEP1 and PEP2 is a peptide sequence that is a nuclear localization sequence and the other is absent.
52. The compound of any one of claims 40-49, wherein SOL1 is the water-solubilizing group and SOL2 is absent.
53. The compound of any one of claims 40-49, wherein each of L1, L2, L3, L4, L5, L6, PEP1, PEP2, and SOL2 is absent, and SOL1 is the water-solubilizing group.
54. The compound of any one of claims 40-53, wherein the water-solubilizing group is a group that contains multiple positive charges at physiological pH.
55. The compound of any one of claims 40-53, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000202_0001
, wherein
Rla is H, alkyl, or a nitrogen atom protecting group;
R2a is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group;
R3a is H, alkyl, or a nitrogen atom protecting group;
R4a is H, alkyl, or a nitrogen atom protecting group;
R5a is alkyl or O-alkyl, any of which is unsubstituted or substituted; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer that is 1-100.
56. The compound of claim 55, wherein p is 5, 6, 7, or 8.
57. The compound of claim 55, wherein p is 7.
58. The compound of any one of claims 40-53, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000203_0001
wherein p is an integer that is 5, 6, 7, or 8.
59. The compound of any one of claims 40-53, wherein the water-solubilizing group of SOL1 is a group of formula:
Figure imgf000203_0002
wherein p is an integer that is 5, 6, 7, or 8.
60. The compound of claim 58 or claim 59, wherein p is 7.
61. The compound of any one of claims 40-60, wherein the heterocycles of the R2 groups are nucleobases or analogues of nucleobases.
62. The compound of any one of claims 40-61, wherein the heterocycles of the R2 groups are each independently:
Figure imgf000203_0003
63. The compound of any one of claims 40-62, wherein each R2 group in the structure is independently:
Figure imgf000204_0001
64. The compound of any one of claims 40-61, wherein the heterocycles of the R2 groups are each independently:
Figure imgf000204_0002
65. The compound of any one of claims 40-61 and 64, wherein each R2 group in the structure is independently:
Figure imgf000204_0003
66. The compound of any one of claims 40-63, wherein the heterocycles of the R2 groups form a sequence that repeats at least twice, wherein the sequence is, from iV-Terminus to C- Terminus:
Figure imgf000204_0004
67. The compound of any one of claims 40-61, 64, and 65, wherein the heterocycles of the R2 groups form a sequence that repeats at least twice, wherein the sequence is, from N- Terminus to C-Terminus:
Figure imgf000205_0001
68. The compound of any one of claims 40-63 and 66, wherein the compound binds to a mRNA sequence transcribed from the gene associated with the neurodegenerative disease phenotype.
69. The compound of any one of claims 40-63 and 66, wherein the compound binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype.
70. The compound of any one of claims 40-63 and 66, wherein the compound binds to a mRNA sequence transcribed from a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of a HTT gene.
71. The compound of any one of claims 40-61, 64, 65, and 67, wherein the compound binds to a DNA sequence of the gene associated with the neurodegenerative disease phenotype.
72. The compound of any one of claims 40-61, 64, 65, and 67, wherein the compound binds to a DNA sequence of a gene associated with a Huntington’s disease phenotype.
73. The compound of any one of claims 40-61, 64, 65, and 67, wherein the compound binds to a DNA sequence of a gene associated with a Huntington’s disease phenotype by interactions between the heterocycles of the R2 groups and nucleobases of a HTT gene.
74. The compound of claim 70 or claim 73, wherein the HTT gene is a non-wild type HTT gene.
75. The compound of claim 74, wherein the non-wild type HTT gene differs from a wild type HTT gene in a repeat expansion mutation.
76. The compound of any one of claims 40-63 and 66, wherein the compound binds to a mRNA sequence of (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
77. The compound of claim 40, wherein the compound is:
Figure imgf000206_0001
or a pharmaceutically-acceptable salt or ionized form thereof.
78. The compound of claim 40, wherein the compound is:
Figure imgf000206_0002
or a pharmaceutically-acceptable salt or ionized form thereof.
79. A compound comprising an oligomeric sequence, wherein the oligomeric sequence comprises a repeating unit of formula:
Figure imgf000207_0001
wherein:
R1 is H, alkyl, or a nitrogen atom protecting group;
R2 is O, NH, N(alkyl), or N(PgN), wherein PgN is a nitrogen atom protecting group; R3 is H, alkyl, or a nitrogen atom protecting group;
R4 is H, alkyl, or a nitrogen atom protecting group;
R5 is alkyl or O-alkyl, any of which is unsubstituted or substituted; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or a pharmaceutically-acceptable salt or ionized form thereof.
80. The compound of claim 79, wherein each of R1, R3, and R4 is hydrogen; and R2 is NH or N(PgN).
81. The compound of claim 79 or claim 80, wherein R5 is linear alkyl.
82. The compound of claim 79 or claim 80, wherein R5 is methyl.
83. The compound of any one of claims 79-82, wherein n is 3.
84. The compound of any one of claims 79-82, wherein n is 4.
85. The compound of any one of claims 79-84, wherein p is 6.
86. The compound of any one of claims 79-84, wherein p is 7.
87. The compound of any one of claims 79-84, wherein p is 8.
88. The compound of claim 1, further comprising a pharmacophore attached to the oligomeric structure, wherein the oligomeric structure, wherein the first chemical moiety, and the second chemical moiety form:
Figure imgf000208_0001
, wherein:
E1 is the pharmacophore, and p is an integer that is 1-100.
89. The compound of claim 88, wherein p is 6.
90. The compound of claim 88, wherein p is 7.
91. The compound of claim 88, wherein p is 8.
92. The compound of any one of claims 88-91, wherein the pharmacophore interferes with expression of a gene associated with a neurodegenerative disease phenotype.
93. The compound of claim 92, wherein the neurodegenerative disease phenotype is a Huntington’s disease phenotype.
94. The compound of claim 93, wherein the Huntington’s disease phenotype is associated with a non-wild-type HTT gene that differs from a wild type HTT gene in a repeat expansion mutation.
95. The compound of any one of claims 88-94, wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CAG)Z, wherein z is an integer from 1-100 (SEQ ID NO: 135).
96. The compound of any one of claims 88-94, wherein the pharmacophore binds to a nucleic acid sequence at a region that is (CTG)Z (SEQ ID NO: 182), wherein z is an integer from 1- 100
97. The compound of any one of claims 88-96, wherein the pharmacophore is an oligonucleotide or oligonucleotide analogue.
98. The compound of any one of claims 88-96, wherein the pharmacophore is a peptide nucleic acid.
99. The compound of claim 88, wherein the compound is:
Figure imgf000209_0001
wherein: each instance of B1, B2, and B3 is independently a heterocycle; each instance of Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl, heteroalkyl, aryl, or heteroaryl, each of which is independently substituted or unsubstituted, or hydrogen;
L3 is a linker group or absent;
C-Terminus is -N(H)-J, wherein J is H, acyl, a group that together with the nitrogen atom to which J is bound forms a carbamate, a probe, a fluorophore, a lipid, a metal chelator, or a biological agent; t is an integer that is from 1 to 30; and t' is an integer that is from 2 to 9, or a pharmaceutically acceptable salt or ionized form thereof.
100. The compound of claim 99, wherein L3 is absent.
101. The compound of claim 99 or claim 100, wherein each instance of Q1, Q2, Q3, Q4, Q5,
Q6, Q7, Q8, Q9, Q10, Q11, Q12, Q13, Q14, Q15, Q16, Q17, and Q18 is independently an amino acid side chain, alkyl that is substituted or unsubstituted, or hydrogen.
102. The compound of claim 99, wherein the compound is:
Figure imgf000210_0001
or a pharmaceutically-acceptable salt or ionized form thereof.
103. A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of any one of claims 1-15 and 22-67.
104. The method of claim 103, wherein the condition is the neurodegenerative disease.
105. The method of claim 103 or claim 104, wherein the condition is associated with a gene having a repeat expansion mutation.
106. The method of any one of claims 103-105, wherein the condition is Huntington’s disease.
107. The method of any one of claims 103-106, wherein the subject is human.
PCT/US2022/032402 2021-06-07 2022-06-06 Peptide nucleic acid therapeutics for trinucleotide repeat disorders WO2022261029A2 (en)

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