KR102339196B1 - Peptide Oligonucleotide Conjugates - Google Patents

Abstract

Oligonucleotide analogs conjugated to a carrier peptide are provided. The disclosed compounds are useful for the treatment of various diseases, for example, those that produce a beneficial therapeutic effect through inhibition of protein expression or modification of abnormal mRNA.

Description

Peptide Oligonucleotide Conjugates {Peptide Oligonucleotide Conjugates}

CROSS REFERENCE TO RELATED APPLICATIONS

This application is filed on May 5, 2011 in U.S. Patent Application No. 13/101,942, and in U.S. Patent Application Serial No. 13/107,528, filed on May 13, 2011, 35 U.S.C. Priority is claimed under § 120, these applications are hereby incorporated by reference in their entirety.

technical field

The present invention relates generally to oligonucleotide compounds (oligomers) useful as antisense compounds, and more particularly to oligomeric compounds conjugated to cell penetrating peptides, and the use of such oligomeric compounds in antisense applications.

The practical utility of many drugs with potentially useful biological activity is often hampered by difficulties in delivering these drugs to their targets. Compounds to be delivered intracellularly must generally be delivered primarily from the aqueous extracellular environment and then penetrate the lipophilic cell membrane to gain entry to the cell. Many molecules, especially large molecules, are either too lipophilic or too hydrophilic for actual solubilization to penetrate the membrane unless the substance is actively transported into a specific transport mechanism.

A segment of the HIV Tat protein (having the sequence RKKRRQRRR (Tat 49 57)) consisting of amino acid residues 49-57 has been used to deliver biologically active peptides and proteins to cells (eg, Barsoum et al. , 1994, PCT Publication No. WO 94/04686) Tat (49 60) has been used to increase the delivery of phosphorothioate oligonucleotides (Astriab-Fisher, Sergueev et al. 2000; Astriab-Fisher, Sergueev). et al. 2002), inverse Tat, or rTat(57-49) (RRRQRRKKR), has been reported to deliver fluorescence into cells with enhanced efficacy compared to Tat (49 57) (Wender, Mitchell et al. 2000; Rothbard, Kreider et al. 2002) Rothbard and Wender also described other arginine-rich transport polymers (PCT Publication No. WO 01/62297; U.S. Patent No. 6,306,993; U.S. Patent Publication No. 2003/0032593).

Oligonucleotides are a class of potentially useful drug compounds and their delivery has often been an obstacle to therapeutic use. Phosphorodiamidate-linked morpholino oligomers (PMOs; see eg Summerton and Weller, 1997) have been found to be more promising in this respect than charged oligonucleotide analogues such as phosphorothioates. PMOs are water-soluble, uncharged or substantially uncharged antisense molecules that inhibit gene expression by preventing splicing or binding or progression of translation machine components. PMO has also been shown to inhibit or block viral replication (Stein, Skilling et al. 2001; McCaffrey, Meuse et al. 2003). They are highly resistant to enzymatic digestion (Hudziak, Barofsky et al. 1996). PMO has been demonstrated in vitro in cell-free and cell culture models (Stein, Foster et al. 1997; Summerton and Weller 1997), and in vivo in zebrafish, frog and urchin knapsacks (Heasman, Kofron et al. 2000; Nasevicius and Ekker 2000) as well as in adult animal models such as rat, mouse, rabbit, dog and pig (eg Arora and Iversen 2000; Qin, Taylor et al. 2000; Iversen 2001; Kipshidze, Keane et al. 2001; Devi 2002; Devi, Oldenkamp et al. 2002; Kipshidze, Kim et al. 2002; Ricker, Mata et al. 2002) demonstrated high antisense specificity and efficacy.

Antisense PMO oligomers are absorbed by cells and have also been shown to be more durable in vivo with less nonspecific effects than other widely used antisense oligonucleotides (see e.g. P. Iversen, "Phosphoramidite Morpholino Oligomers", in Antisense Drug Technology, ST Crooke, ed., Marcel Dekker, Inc., New York, 2001). Conjugation of PMO to arginine-rich peptides has been shown to increase their cell uptake (see, for example, US Pat. No. 7,468,418). However, the toxicity of the conjugates has slowed their development as available drug candidates.

Although significant advances have been made, there remains a need in the art for oligonucleotide conjugates with improved antisense or antigenic performance. These improved antisense or antigen performance include lower toxicity, stronger affinity for DNA and RNA that do not match sequence selectivity; improved pharmacokinetics and tissue distribution; improved cell delivery and reliable and controllable ex vivo distribution.

The compounds of the present invention address these problems and provide improvements over existing antisense molecules in the art. By linking a cell penetrating peptide to a substantially uncharged nucleic acid analog via a glycine or proline amino acid, we addressed the toxicity problem associated with other peptide oligomeric conjugates. Moreover, modifications of intersubunit linkages and/or conjugation of terminal sites to the 5' and/or 3' ends of oligonucleotide analogs, such as morpholino oligonucleotides, may also improve the properties of the conjugate. For example, the conjugates described in certain embodiments may have reduced toxicity and/or increased cellular delivery, potential, and/or tissue distribution and/or more effective delivery to target organs compared to other oligonucleotide analogs. have. These superior properties result in advantageous therapeutic indexes, reduced clinical dosing and lower cost of the product.

Accordingly, in one embodiment, the present invention provides

(a) a carrier peptide comprising an amino acid subunit; and

(b) a nucleic acid analog comprising a substantially uncharged backbone and a target nucleotide sequence for sequence-specific binding to a target nucleic acid

It is a conjugate (conjugate) comprising a,

wherein at least two of the amino acid subunits are positively charged amino acids, and the carrier peptide comprises a glycine (G) or proline (P) amino acid at the carboxy terminus of the carrier peptide; Also provided is a conjugate wherein the carrier peptide is covalently attached to the nucleic acid analog. Also provided are compositions comprising the conjugates and pharmaceutically acceptable excipients.

In another embodiment, the invention provides a method of inhibiting the production of a protein comprising exposing a nucleic acid encoding the protein to a conjugate of the invention.

Another aspect of the present invention is a method for enhancing the transport of a nucleic acid analogue into a cell, comprising the step of conjugating the carrier peptide of claim 1 to the nucleic acid analogue, wherein the transport of the nucleic acid analogue into the cell is not conjugated. Including a method that is augmented compared to

In another embodiment, the present invention relates to a method of treating a disease in a subject comprising administering to the subject a therapeutically effective amount of a described conjugate. Methods for making the conjugates, methods for their use, and carrier peptides useful for conjugation to nucleic acid analogs are also provided.

These and other objects of the present invention will become apparent with reference to the following detailed description. For this purpose, various publications are described herein which set forth in more detail certain background information, procedures, compounds and/or compositions, each of which is incorporated herein by reference in its entirety.

1A depicts an exemplary morpholino oligomer structure comprising phosphorodiamidate linkages.
1B depicts a morpholino oligomer conjugated to a carrier peptide at the 5' end.
1C depicts a morpholino oligomer conjugated to a carrier peptide at the 3' end.
1D-G depict repeating subunit segments of exemplary morpholino oligonucleotides designated 1D-1G.
2 depicts exemplary intersubunit linkages bound to a morpholino-T moiety.
3 is a scheme showing the preparation of a linker for solid-phase synthesis.
Figure 4 demonstrates the preparation of a solid support for oligomer synthesis.
5A, 5B and 5C show exon skipping data for exemplary conjugates compared to known conjugates in mouse quadriceps, diaphragm and heart, respectively.
6A, 6B and 6C are alternate representations of exon skipping data for exemplary conjugates compared to known conjugates in mouse quadriceps, diaphragm and heart, respectively.
7A and 7B are graphs showing blood urea nitrogen (BUN) levels and survival rates of mice treated with various peptide-oligomer conjugates, respectively.
8A and 8B show the kidney injury marker (KIM) data and clusterrin (Clu) of mice treated with various peptide-oligomer conjugates, respectively.
9A, 9B, 9C and 9D are graphs comparing exon skipping, BUN levels, survival and KIM levels, respectively, in mice treated with exemplary conjugates compared to known conjugates.
10 shows KIM data of mice treated with various zygotes.
11 shows the results of BUN analysis of mice treated with various zygotes.
12 is a graph showing the concentration of various oligomers in mouse kidney tissue.

1. Definition

In the following description, specific specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail in order to avoid unnecessarily obscuring descriptions of embodiments. Throughout the following specification and claims, unless the context requires otherwise, the word "comprises" and variations thereof such as "comprises" and "comprising" are open-ended; It should be construed in its inclusive sense, i.e. "including but not limited to". Additionally, the introduction provided herein is for convenience only and does not interpret the scope or meaning of the claimed invention.

Reference throughout the specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, a particular feature, structure, or characteristic may be combined in any suitable way in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a" (a, an) and "the" (the) include plural references unless the context clearly dictates otherwise. The term “or” is generally used in its sense including “and/or” unless the context clearly dictates otherwise.

As used herein, the following terms have the following meanings unless otherwise indicated.

“Amino” refers to the —NH ₂ radical.

"Cyano" or "nitrile" refers to a radical.

"Hydroxy" or "hydroxyl" refers to a radical.

“Imino” refers to the =NH substituent.

“Guanidyl” refers to a —NHC(=NH)NH ₂ substituent.

“Amidinyl” refers to a —C(=NH)NH ₂ substituent.

“Nitro” refers to the —NO ₂ radical.

"Oxo" refers to the =O substituent.

"Thioxo" refers to the =S substituent.

"Choleate" refers to the structure:

"Deoxycholate" refers to the structure:

"Alkyl" refers to a straight or branched hydrocarbon chain radical that is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), has 1 to 30 carbon atoms, and is attached to the remainder of the molecule by a single bond. . Alkyl containing any number of carbon atoms from 1 to 30 is included. Alkyl containing up to 30 carbon atoms _{is referred to as C 1} -C ₃₀ alkyl, likewise, for example, alkyl containing up to 12 carbon atoms is C ₁ -C ₁₂ alkyl. Alkyl (and other moieties as defined herein) containing other numbers of carbon atoms are similarly indicated. Alkyl group is, C ₁ -C ₃₀ alkyl, C ₁ -C ₂₀ alkyl, C ₁ -C ₁₅ alkyl, C ₁ -C ₁₀ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl, C ₂ -C ₈ alkyl, C ₃ -C ₈ alkyl and C ₄ -C ₈ alkyl. Representative alkyl groups are methyl, ethyl, n -propyl, 1-methylethyl (iso-propyl), n -butyl, i -butyl, s -butyl, n -pentyl, 1,1-dimethylethyl ( t -butyl), 3 -Methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, but-2- inyl, but-3-ynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. Alkylene may be saturated or unsaturated (ie, it contains one or more double and/or triple bonds). Representative alkylenes are C ₁ -C ₁₂ alkylene, C ₁ -C ₈ alkylene, C ₁ -C ₆ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₃ alkylene, C ₁ -C ₂ alkyl ene, C ₁ alkylene, but is not limited thereto. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, n -butylene, ethenylene, propenylene, n-butenylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain may be optionally substituted as described below.

“Alkoxy” refers to _a radical of the formula-OR a , wherein R _a is alkyl as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below.

“Alkoxyalkyl” refers to _{a radical of the formula —R b} OR a , wherein R _a is an alkyl radical as defined and R _b is an alkylene radical as defined. Unless stated otherwise specifically in the specification, an alkoxyalkyl group may be optionally substituted as described below.

_{"Alkylcarbonyl" refers to a} radical of the formula -C(=O)R a , wherein R _a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylcarbonyl group may be optionally substituted as defined below.

_{"Alkyloxycarbonyl" refers to a} radical of -C(=O)OR a , wherein R _a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkyloxycarbonyl group may be optionally substituted as defined below.

"Alkylamino" refers to _{a radical of the formula -NHR a} or -NR _a R a , wherein each R _a is independently an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as defined below.

_{"Amidyl" refers to a} radical of the formula -N(H)C(=O)R a , wherein R _a is an alkyl or aryl radical as defined herein. Unless stated otherwise specifically in the specification, an amidyl group may be optionally substituted as defined below.

“Amidinylalkyl” refers to a radical _{of the formula —R b} —C(=NH)NH _{2 , wherein R b} is an alkylene radical as defined above. Unless stated otherwise specifically in the specification, an amidinylalkyl group may be optionally substituted as defined below.

"Amidinylalkylcarbonyl" refers to a radical of the formula -C(=O)R _b -C(=NH)NH _{2 , wherein R b} is an alkylene radical as defined above. Unless stated otherwise specifically in the specification, an amidinylalkylcarbonyl group may be optionally substituted as defined below.

"Aminoalkyl" refers to _{a radical of the formula -R b} -NR _a R a , wherein R _b is an alkylene radical as defined above and each R _a is independently hydrogen or an alkyl radical.

“Thioalkyl” refers to _a radical of the formula —SR a , wherein R _a is alkyl as defined above. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

"Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals are aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoroantene, fluorene, as -indacene, s -indacene, indane, indene, naphthalene, aryl radicals derived from phenalene, phenanthrene, pleiadene, pyrene and triphenylene. Unless stated otherwise specifically herein, the term “aryl” or the prefix “ar-” (eg “aralkyl”) is meant to include an aryl radical that is optionally substituted.

"Aralkyl" refers to a radical _{of the formula -R b} -R _{c , wherein R b} is an alkylene chain as defined above and R _c is one or more aryl radicals as defined above, for example benzyl , diphenylmethyl, trityl, and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

"Arylcarbonyl" refers to a group of the formula -C(=O)R _c , wherein R _c is one or more aryl radicals as defined above, for example phenyl. Unless stated otherwise specifically in the specification, an arylcarbonyl group may be optionally substituted.

"Aryloxycarbonyl" refers to a radical of the formula -C(=O)OR _{c , wherein R c} is one or more aryl radicals as defined above, for example phenyl. Unless stated otherwise specifically in the specification, an aryloxycarbonyl group may be optionally substituted.

"Aralkylcarbonyl" refers to a radical of the formula -C(=O)R _b -R _{c , wherein R b} is an alkylene chain as defined above and R _c is one or more as defined above an aryl radical, for example phenyl. Unless stated otherwise specifically in the specification, an aralkylcarbonyl group may be optionally substituted.

"Aralkyloxycarbonyl" refers to a radical of the formula -C(=O)OR _b -R _{c , wherein R b} is an alkylene chain as defined above and R _c is one as defined above or more aryl radicals, for example phenyl. Unless stated otherwise specifically in the specification, an aralkyloxycarbonyl group may be optionally substituted.

“Aryloxy” refers to a radical _{of the formula —OR c , wherein R c} is one or more aryl radicals as defined above, for example phenyl. Unless stated otherwise specifically in the specification, an arylcarbonyl group may be optionally substituted.

"Cycloalkyl" denotes a stable, non-aromatic, monocyclic or polycyclic ring, which may include fused or bridged ring systems, is saturated or unsaturated, and is attached to the remainder of the molecule by a single bond. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms and 3 to 8 carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless stated specifically in the specification, a cycloalkyl group may be optionally substituted.

“Cycloalkyl” refers to a radical _{of the formula —R b} R _{d , wherein R b} is alkylene as defined above and R _d is a cycloalkyl radical as defined above. Unless stated specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

"Cycloalkylcarbonyl" refers to a radical of the formula -C(=O)R _{d , wherein R d} is a cycloalkyl radical as defined above. Unless stated specifically in the specification, a cycloalkylcarbonyl group may be optionally substituted.

"Cycloalkyloxycarbonyl" refers to a radical of the formula -C(=O)OR _{d , wherein R d} is a cycloalkyl radical as defined above. Unless stated specifically in the specification, a cycloalkyloxycarbonyl group may be optionally substituted.

"Fused" refers to any ring structure described herein that is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring may be substituted with a nitrogen atom.

“Guanidinylalkyl” refers to a radical _{of the formula —R b} —NHC(=NH)NH _{2 , wherein R b} is an alkylene radical as defined above. Unless stated specifically in the specification, a guanidinylalkyl group may be optionally substituted as described below.

"Guanidinylalkylcarbonyl" refers to a radical of the formula -C(=O)R _b -NHC(=NH)NH _{2 , wherein R b} is an alkylene radical as defined above. Unless stated specifically in the specification, a guanidinylalkylcarbonyl group may be optionally substituted as described below.

"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

"Haloalkyl" refers to an alkyl radical as defined above which is substituted by one or more halo radicals as defined above, for example trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2, 2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. are shown. Unless stated specifically in the specification, a haloalkyl group may be optionally substituted.

"Perhalo" or "perfluoro" denotes a moiety in which each hydrogen atom is replaced by a halo atom or a fluoro atom, respectively.

"Heterocyclyl", "heterocycle" or "heterocyclic ring" is a stable 3-membered to containing 1 to 8 heteroatoms and 2 to 23 carbon atoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. 24-membered non-aromatic ring radical. Unless stated specifically herein, a heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; Also in the heterocyclyl radical the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; The heterocyclyl radical may also be partially or fully saturated. Examples of such heterocyclyl radicals include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, ioxazolidinyl, morphol nyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl , pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1 , 1-dioxo-thiomorpholinyl, 12-crown-4,15-crown-5,18-crown-6,21-crown-7, aza-18-crown-6, diaza-18-crown- 6, aza-21-crown-7, and diaza-21-crown-7. Unless stated otherwise in the specification, a heterocyclyl group may be optionally substituted.

"Heteroaryl" refers to a 5- to 14-membered ring system radical comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring indicates. For the purposes of the present invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; Also the nitrogen, carbon or sulfur atom in said heteroaryl radical may optionally be oxidized; The nitrogen atom may optionally be quaternized. Examples thereof include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[ b ][ 1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranoyl, benzofuranyl, benzofura Noyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl , furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridi nyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1- Phenyl-1 H -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, furinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, Quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, trizolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl), but are not limited thereto. Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

All of the above groups may be substituted or unsubstituted. As used herein, the term “substituted” refers to any of the above groups (eg, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycarbonyl, alkylamino, amidyl, amidinylalkyl, amidi Nylalkylcarbonyl, aminoalkyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyl alkylcarbonyl, cycloalkyloxycarbonyl, guanidinylalkyl, guanidinylalkylcarbonyl, haloalkyl, heterocyclyl and/or heteroaryl) may be further functionalized, wherein at least one hydrogen It means that an atom can be replaced by a non-hydrogen atom substituent by a bond. Unless stated otherwise herein, a substituted group is oxo, -CO ₂ H, nitrile, nitro, -CONH ₂ , hydroxyl, thiooxy, alkyl, alkylene, alkoxy, alkoxyalkyl, alkylcarbonyl, alkyloxycar Bornyl, aryl, aralkyl, arylcarbonyl, aryloxycarbonyl, aralkylcarbonyl, aralkyloxycarbonyl, aryloxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, cycloalkyl oxycarbonyl, heterocyclyl, heteroaryl, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; A silicon atom in the group, for example a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a perfluoroalkyl or perfluoroalkoxy group, for example a trifluoromethyl or trifluoro one or more substituents selected from romethoxy. "Substituted" also refers to heteroatoms such as oxygen in oxo, carbonyl, carboxyl, and ester groups in which one or more hydrogen atoms are linked by higher-order bonds (eg, double or triple bonds); means any of the above groups which can be replaced by nitrogen, oxime, hydranzine and nitrile in groups such as imine. For example, "substituted" means that one or more hydrogen atoms are -NR _g C(=O)NR _g R _h , -NR _g C(=O)OR _h , -NR _g SO ₂ R _h , -OC(=O )NR _g R _h , -OR _g , -SR _g , -SOR _g , -SO ₂ R _g , -OSO ₂ R _g , -SO ₂ OR _g , =NSO ₂ R _g , and -SO ₂ NR _g R _h includes any of the above groups replaced by "Substituted" also means that one or more hydrogen atoms are -C(=O)R _g , -C(=O)OR _g , -CH ₂ SO ₂ R _g , -CH ₂ SO ₂ NR _g R _h , -SH, - SR _g or any of the above groups replaced by _{-SSR g.} In the foregoing, R _g and R _h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N -heterocyclyl, heterocyclylalkyl, heteroaryl, N -heteroaryl and/or heteroarylalkyl. In addition, each of the substituents described above may also be optionally substituted with one or more of those substituents. Moreover, any of the above groups may be substituted to include one or more internal oxygen or sulfur atoms. For example, an alkyl group may be substituted with one or more internal oxygen to form an ether or polyether group. Similarly, an alkyl group may be substituted with one or more internal sulfur atoms to form thioethers, disulfides, and the like. The amidyl moiety may be substituted with up to two halo atoms, while other such groups may be substituted with one or more halo atoms. Any of the above groups may also be substituted with amino, monoalkylamino, guanidinyl or amidinyl. Optional substituents for any of the above groups also include arylphosphoryl, eg, of the formula -R _a P(Ar) ₃ , wherein R _a is alkylene and Ar is an aryl moiety, eg, phenyl.

The terms "antisense oligomer" or "antisense compound" are used interchangeably and also refer to a sequence of subunits, each having a base carried on a backbone subunit composed of ribose or other pentose sugars or morpholino groups, , wherein the backbone group hybridizes a base in a compound to a target sequence in a nucleic acid (typically RNA) by Watson-Crickare base pairing, and a nucleic acid: oligomeric heteroduplex in the target sequence. connected by The oligomer may have exact sequence complementarity or approximate complementarity to the target sequence. Such antisense oligomers are designed to block or inhibit translation of mRNA comprising a target sequence and may also be referred to as "associating" with a hybridizing sequence.

A “morpholino oligomer” or “PMO” refers to a polymer molecule that supports a base capable of hydrogen bonding to a representative polynucleotide, wherein the polymer comprises a pentose sugar backbone moiety and more specifically nucleotides and nucleosides. It does not contain a ribose backbone linked by a representative phosphodiester bond, but instead contains a ring nitrogen with coupling through the ring nitrogen. Exemplary "morphrolpino" oligomers are linked together by (thio)phosphoramidate or (thio)phosphorodiamidate bonds, one subunit of morpholino nitrogen at the 5' exocyclic carbon of the adjacent subunit. morpholino subunit structures that bind to, each comprising a purine or pyrimidine base-pairing moiety effective for linking to a base in a polynucleotide by base-specific hydrogen bonding. Morpholino oligomers (including antisense oligomers) are described, for example, in U.S. Patent Nos. 5,698,685; 5,217,866; 5,142,047; 5,034,506; 5,166,315; 5,185,444; 5,521,063; 5,506,337 and pending US Patent Application Nos. 12/271,036; 12/271,040; and PCT International Publication No. WO/2009/064471, all of which are incorporated herein by reference in their entirety. Representative PMOs include PMOs in which the small intermolecular bond is a bond (A1).

"PMO+" refers to any number of (1-piperazino)phosphonylideneoxy, (1-(4-(ω-guanidino-alkanoyl)-piperazino)phosphiniledeneoxy linkages described above phosphorodiamidate morpholino oligomers comprising (A2 and A3) (see, eg, PCT International Application Publication No. WO/2008/036127, herein incorporated by reference in its entirety).

"PMO-X" refers to a phosphorodiamidate described herein comprising at least one (B) bond or at least one described terminal modification.

A "phosphoramidate" group contains three attached oxygen atoms and one attached nitrogen atom, whereas a "phosphorodiamidate" group (see e.g. Figures 1D-E) has two attached oxygen atoms. and phosphorus having two attached nitrogen atoms. In the uncharged or modified intersubunit linkages of oligomers described herein and in pending US patent applications 61/349,783 and 11/801,885, one nitrogen is always suspended from the backbone chain. The second nitrogen in the phosphorodiamidate bond is typically the ring nitrogen in the morpholino ring structure.

A “thiophosphoramidate” or “thiophosphorodiamidate” bond is a phosphoramidate or phosphorodiamidate, respectively, wherein one oxygen atom, typically the oxygen hanging from the backbone, is replaced with sulfur.

"Intersubunit bond" refers to a bond comprising two morpholino subunits, for example of formula (I).

The terms “uncharged,” “cationic,” and “anionic,” as used herein, refer to the dominant state of a chemical moiety at an approximate neutral pH, eg, about 6 to 8. For example, the term may refer to the principal state of a chemical moiety at physiological pH, ie, about 7.4.

"Lower alkyl" denotes an alkyl radical of 1 to 6 carbon atoms, such as methyl, ethyl, n-butyl, i-butyl, t-butyl, isoamyl, n-pentyl and isopentyl. In certain embodiments, a “lower alkyl” group has from 1 to 4 carbon atoms. In other embodiments, a “lower alkyl” group has 1 to 2 carbon atoms, i.e., methyl or ethyl. Similarly, "lower alkenyl" denotes an alkenyl radical of 2 to 6, preferably 3 or 4 carbon atoms, such as allyl and butenyl.

A “non-interfering substituent” is one that adversely affects the ability of an antisense oligomer as described herein to bind to its intended target. Such substituents include small and/or relatively non-polar groups such as methyl, ethyl, methoxy, ethoxy or fluoro.

An oligonucleotide or antisense oligomer is formed when said oligomer hybridizes to a target under physiological conditions having a Tm of at least 37°C, at least 45°C, preferably at least 50°C, and typically 60°C-80°C or higher. "specifically hybridizes" to a nucleotide. The “Tm” of an oligomer is the temperature at which it hybridizes to 50% complementary polynucleotides. Tm is described, for example, in Miyada et al ., Methods Enzymol . 154 :94-107 (1987) under standard conditions in physiological saline. Such hybridization can occur with exact complementarity as well as "near" or "substantial" complementarity of the antisense to the target sequence.

Polynucleotides are described as "complementary" to each other when hybridization occurs in an antiparallel configuration between two single-stranded polynucleotides. Complementarity (the degree to which one polynucleotide is complementary to another) can be quantified in terms of the proportion of bases in opposite strands that are expected to form hydrogen bonds with each other according to generally accepted base pairing rules.

A first sequence is an “antisense sequence” with respect to a second sequence if the polynucleotide specifically binds or specifically hybridizes to the second polynucleotide sequence under physiological conditions with the first sequence.

The term "target sequence" is a sequence in an oligonucleotide analog that is complementary (in addition, substantially complementary in meaning) to a target sequence in the RNA genome. The entire sequence, or only a portion, of the analog compound may be complementary to the target sequence. For example, in an analog having 20 bases, only 12-14 may be the target sequence. Typically, a target sequence forms contiguous bases in an analog, but can alternatively form non-contiguous sequences that make up a sequence that spans the target sequence, for example, when placed together from opposite ends of the analog. have.

The "backbone" of an oligonucleotide analog (eg, an uncharged oligonucleotide analog) refers to a structure that supports base pairing moieties for morpholino oligomers, eg, as described herein. The "backbone" includes morpholino ring structures linked by small intermolecular bonds (eg, phosphorus-containing bonds). "Substantially uncharged backbone" refers to the backbone of an oligonucleotide analog, wherein less than 50% of the small intermolecular bonds are charged at near neutral pH. For example, a substantially uncharged backbone exhibits less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or even 0% of intersubunit bonding that is charged near neutral pH. may include In some embodiments, a substantially uncharged backbone comprises at most one charged intermolecular bond (at physiological pH) at most one charged intermolecular bond (at physiological pH) for every 4 uncharged bonds (at physiological pH), 1 for every 8 or at most 1 for every 16 uncharged bonds. In some embodiments, the nucleic acid analogs described herein are fully uncharged.

A target and a target sequence are described as being "complementary" to each other when hybridization occurs in antiparallel structures. A target sequence may have "near" or "substantial" complementarity to the target sequence and also serves the purposes of the methods described herein, ie, is still "complementary". Preferably, the oligonucleotide analog compound used in the method described herein has at most one mismatch with the target sequence every 10 nucleotides, and preferably at most one mismatch out of 20. Alternatively, the antisense oligomers used have at least 80%, at least 90% sequence homology or at least 95% sequence homology with an exemplary target sequence as described herein. For the purpose of complementary binding to the RNA target, as described below, a guanine base may be complementary to a cytosineor uracil RNA base.

"Heteroduplex" refers to a duplex between an oligonucleotide analog and a complementary portion of a target RNA. "Nuclease-resistant heteroduplex" refers to a heteroduplex formed by the binding of an antisense oligomer to its complementary target, such that the heteroduplex is capable of cleaving, for example, double-stranded RNA/RNA or RNA/DNA complexes. It is substantially resistant to in vivo digestion by intracellular and extracellular nucleases such as RNAse H.

A drug is "actively taken up by mammalian cells" when it enters the cell by a mechanism rather than passive diffusion across the cell membrane. A drug may be transported, for example, by "active transport", which refers to transport of the drug across mammalian cell membranes, for example by an ATP-dependent transport mechanism or by "facilitated transport", transport It represents the transport of the antisense drug across the cell membrane by a transport mechanism that requires binding of the drug to the protein and then facilitates the passage of the binding agent across the membrane.

The terms “regulated expression” and/or “antisense activity” refer to the ability to interfere with the expression or translation of RNA to increase or more typically decrease the expression of a given protein. In the case of reduced protein expression, the antisense oligomer may directly block the expression of a given gene, or contribute to the promotion of destruction of RNA transcribed from the gene. Morpholino oligomers as described herein are believed to act through the former (steric blocking) mechanism. Preferred antisense targets for steric blocking oligomers are the ATG start codon region, the splice site, the region closely adjacent to the splice site, and the 5'- of mRNA, although other regions are successfully targeted using the morpholino oligomer. Includes untranslated regions.

An "amino acid subunit" is generally an amino acid residue (-CO-CHR-NH-); β- or other amino acid residues (eg, -CO-CH ₂ CHR-NH-), where R is an amino acid side chain.

The term “naturally occurring amino acid” refers to an amino acid that is present in proteins found in nature. The term “unnatural amino acid” refers to an amino acid that is not present in proteins found in nature and includes, for example, beta-alanine (β-Ala) and 6-aminohexanoic acid (Ahx).

An “effective amount” or “therapeutically effective amount” is an amount of antisense oligomer administered to a mammal either as a single dose or as part of a series of doses effective to produce the desired therapeutic effect, typically by inhibiting translation of a selected target nucleic acid sequence. indicates

"Treatment" of a subject (eg, a mammal, such as a human) or cell is any type of interference used in an attempt to alter the natural process of the subject or cell. Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may also be carried out prophylactically or after the onset of a pathological event or after contact with the pathogen.

II. carrier peptide

A, properties of carrier peptides

As noted above, the present invention relates to a conjugate of a carrier peptide and a nucleic acid analog. Carrier peptides are generally effective in enhancing cellular penetration of nucleic acid analogs. Moreover, Applicants have surprisingly found that inclusion of a glycine (G) or proline (P) amino acid between the nucleic acid analog and the rest of the carrier peptide (e.g., at the carboxy or amino terminus of the carrier peptide) reduces the toxicity of the conjugate, whereas the efficacy is It has been found to remain the same or increase for conjugates with different binding between the carrier protein and the nucleic acid analog. Therefore, the conjugate of the present invention has a better therapeutic window than other peptide-oligomer conjugates and is a more promising drug candidate.

In addition to reduced toxicity, the presence of glycine or proline amino subunits between the nucleic acid analog and the carrier protein is believed to provide additional advantages. For example, glycine is inexpensive and readily couples to nucleic acid analogs (or optional linkers) without any possibility of racemization. Similarly, proline couples readily without racemization and also provides a carrier peptide that is not a helix former. The hydrophobicity of proline may also confer certain advantages with respect to the interaction of the cell's lipid bilayer with the carrier peptide. A carrier peptide comprising multiple prolines (eg in certain embodiments) may resist G-tetraplex formation. Finally, in certain embodiments, when the proline moiety is adjacent to an arginine amino acid subunit, the proline moiety confers metabolism to the conjugate because the arginine-proline amide bond cannot be cleaved by a common endopeptidase.

As noted above, a conjugate comprising a carrier protein linked to a nucleic acid analog via a glycine or proline amino acid subunit has low toxicity and similar efficacy compared to other known conjugates. Experiments performed in support of the present application show that the renal toxicity markers are significantly lower in the conjugates of the present invention compared to other conjugates (e.g., the renal impairment marker (KIM) and blood urea nitrogen described in Example 30). (BUN) see data). While not wishing to be bound by theory, the inventors believe that the reduced toxicity of the described conjugates is combined with the absence of a non-natural amino acid such as aminohexanoic acid or β-alanine in the portion of the peptide attached to the nucleic acid analog (eg, the carboxy terminus); I believe it could be related. Since these unnatural amino acids are not cleaved in vivo, it is thought that toxic concentrations of uncleaved peptides may accumulate and cause toxic effects.

The glycine or proline moiety may be the amino or carboxy terminus of the carrier peptide, and in some cases, the carrier peptide may be linked directly to the nucleic acid analog via a glycine or proline subunit or the carrier peptide may be linked to the nucleic acid analog via an optional linker. have.

In one embodiment, the present invention provides

(a) a carrier peptide comprising an amino acid subunit; and

(b) a nucleic acid derivative comprising a substantially uncharged backbone and a target nucleotide sequence for sequence-specific binding to a target nucleic acid

It is a conjugate (conjugate) comprising a,

wherein at least two of the amino acid subunits are positively charged amino acids, the carrier peptide comprises a glycine (G) or proline (P) amino acid subunit at the carboxy terminus of the carrier peptide, and the carrier peptide is covalently attached to a nucleic acid analog. It provides a conjugate to which it is attached. In some embodiments, no more than 7 contiguous amino acid subunits are arginine, eg, 6 or fewer contiguous amino acid subunits are arginine. In some embodiments, the carrier peptide comprises a glycine amino acid subunit at the carboxy terminus. In another embodiment, the carrier peptide comprises a proline amino acid subunit at the carboxy terminus. In another embodiment, the carrier peptide comprises a single glycine or proline at the carboxy terminus (ie no glycine or proline dimers or trimers at the carboxy terminus).

In certain embodiments, the carrier peptide, when conjugated to an antisense oligomer having a substantially uncharged backbone, has its target sequence relative to the antisense oligomer in its unconjugated form, as evidenced by (i) or (ii) below. It is effective in increasing the binding of antisense oligomers to:

(i) a decrease in the expression of the encoded protein relative to that provided by the unconjugated oligomer, if binding of the antisense oligomer to its target sequence is effective to block the translation start codon of the encoded protein, or

(ii) expression of the encoding protein relative to that provided by the unconjugated oligomer if the binding of the antisense oligomer to its target sequence is effective to block aberrant splice sites in the pre-mRNA encoding the protein when spliced correctly increase in. Assays suitable for the measurement of these effects are further described below. In one embodiment, conjugation of the peptide provides such activity in a cell-free translation assay as described herein. In some embodiments, the activity is enhanced by at least 2 factors, at least 5 factors, or at least 10 factors.

Alternatively or additionally, the carrier peptide is effective to increase transport of the nucleic acid analog into a cell as compared to the analog in its unconjugated form. In certain embodiments, transport is enhanced by at least 2 factors, at least 5 factors, or at least 10 factors.

In another embodiment, the carrier protein is effective in reducing the toxicity of the conjugate (ie, increasing the maximum tolerated dose) with respect to the conjugate comprising a carrier peptide lacking the terminal glycine or proline amino subunits. In certain embodiments, toxicity is reduced by at least 2 factors, at least 5 factors, or at least 10 factors.

A further advantage of the peptide transport site is its expected ability to stabilize the duplex between the antisense oligomer and its target nucleic acid sequence. Without wishing to be bound by theory, this ability to stabilize the duplex may result from electrostatic interactions between the positively charged transport site and the negatively charged nucleic acid.

The length of the carrier protein is not particularly limited and also varies in different embodiments. In some embodiments, the carrier peptide comprises 4 to 40 amino acid subunits. In other embodiments, the carrier peptide comprises 6-30, 6-20, 8-25 or 10-20 amino acid subunits. In some embodiments, the carrier peptide is straight chain, while in other embodiments it is branched.

In some embodiments, the carrier peptide is enriched in positively charged amino acid subunits, eg, arginine amino acid subunits. The carrier peptide is "enriched" in positively charged amino acids when at least 10% of the amino acid subunits are positively charged. For example, in some embodiments, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the amino acid subunits are positively charged. In another embodiment, all amino acid subunits, except for the glycine or proline amino acid subunits, are positively charged. In another embodiment, all of the positively charged amino acid subunits are arginine.

In other embodiments, the number of positively charged amino acid subunits in the carrier peptide ranges from 1 to 20, such as from 1 to 10 or from 1 to 6. In certain embodiments, the number of positively charged amino acids in the carrier peptide is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19 or 20.

A positively charged amino acid may be a naturally occurring, non-naturally occurring, synthetic, modified, or analog of a naturally occurring amino acid. For example, modified amino acids with a net positive charge may be specifically designed for use in the present invention in the more detailed description below. Many different types of modifications to amino acids are well known in the art. In certain embodiments, the positively charged amino acid is histidine (H), lysine (K) or arginine (R). In other embodiments, the carrier peptide comprises only natural amino acid subunits (ie, contains no unnatural amino acids). In other embodiments, the terminal amino acid may be capped at, for example, the N-terminus with, for example, an acetyl, benzoyl or stearyl moiety.

Any number, combination and/or sequence of H, K and/or R may be present in the carrier peptide. In some embodiments, all of the amino acid subunits are positively charged amino acids except for the carboxyl terminal glycine or proline. In another embodiment, at least one of the positively charged amino acids is arginine. For example, in some embodiments, all of the positively charged amino acids are arginine, and in still other embodiments, the carrier peptide consists of arginine and the carboxy terminal glycine or proline. In another embodiment, the carrier peptide comprises no more than 7 contiguous arginines, for example no more than 6 contiguous arginines.

Other types of positively charged amino acids are also contemplated. For example, in certain embodiments, at least one of the positively charged amino acids is an arginine analog. For example, the arginine analog can be a cationic α-amino acid comprising a side chain ^{of the formula R a} N=C(NH ₂ )R ^{b , wherein R a} is H or R ^c ; R ^b is R ^c , NH ₂ , NHR, or N(R ^c ) ₂ , R ^c is lower alkyl or lower alkenyl, optionally comprising oxygen or nitrogen, or R ^a and R ^b together form a ring and the side chain is linked to an amino acid via ^{R a} or R ^{b .} The carrier peptide may include any number of these arginine analogs.

A positively charged amino acid may occur in any sequence within the carrier peptide. For example, in some embodiments, the positively charged amino acids may be alternating or may be sequential. For example, the carrier peptide may comprise the sequence (R ^d ) _m , wherein R ^d at each occurrence is independently a positively charged amino acid and m is 2 to 12, 2 to 10, 2 to 8 or 2 to 6 An integer in the range. For example, in certain embodiments, R ^d is arginine and the carrier peptide is a _{sequence selected from (R) 4} , (R) ₅ , (R) ₆ , (R) ₇ and (R) ₈ or (R) ₄ , (R) ₅ , (R) ₆ and (R) ₇ , for example in a specific embodiment the carrier peptide comprises the sequence (R) ₆ , such as (R) ₆ G or (R) ) contains _{6 P.}

In another embodiment, the carrier peptide comprises the sequence (R ^d ) _m and the carboxyl terminal glycine or proline, wherein R ^d at each occurrence is independently a positively charged amino acid, and m is 2-12, 2-10, an integer ranging from 2 to 8 or 2 to 6. In certain embodiments, Rd at each occurrence is independently arginine, histidine, or lysine. For example, in certain embodiments R ^d is arginine and the carrier peptide is a _{sequence selected from (R) 4} , (R) ₅ , (R) ₆ , (R) ₇ and (R) ₈ and a carboxy terminal glycine or It is made up of proline. For example, in a specific embodiment, the carrier peptide consists of the sequence (R) ₆ G or (R) ₆ P.

In some other embodiments, the carrier peptide may comprise one or more hydrophobic amino acid subunits, said hydrophobic amino acid subunits comprising a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or aralkyl side chain, wherein said alkyl , alkenyl and alkynyl side chains contain at most one heteroatom for every 6 carbon atom acid. In some embodiments, the hydrophobic amino acid is phenylalanine (F). For example, the carrier peptide may comprise two or more contiguous hydrophobic amino acids such as phenylalanine (F), for example two contiguous phenylalanine sites. The hydrophobic amino acid(s) may be present at any point in the carrier peptide sequence.

In other embodiments, the carrier peptide comprises the sequence [(R ^d Y ^b R ^d ) _x (R ^d R ^d Y ^b ) _y ] _z , or [(R ^d R ^d Y ^b ) _y (R ^d Y ^b R ^d ) _x ] _z wherein R ^d at each occurrence is independently a positively charged amino acid, x and y at each occurrence are independently 0 or 1, with the proviso that x + y is 1 or 2 and z is 1 , 2, 3, 4, 5 or 6 and Y ^b is of the formula:

wherein n is 2 to 7 and each R ^e at each occurrence is independently hydrogen or methyl. In some of these embodiments, R ^d at each occurrence is independently arginine, histidine, or lysine. In other embodiments, each R ^d is arginine. In another embodiment, n is 5 and Y ^b is an aminohexanoic acid moiety. In another embodiment, n is 2 and Y ^b is a β-alanine moiety. In another embodiment, R ^e is hydrogen.

In certain embodiments of the foregoing, x is 1 and y is 0 and the carrier peptide comprises the sequence (R ^d Y ^b R ^d ) _z . In another embodiment, n is 5 and Y ^b is an aminohexanoic acid moiety. In another embodiment, n is 2 and Y ^b is a β-alanine moiety. In another embodiment, R ^e is hydrogen.

In another embodiment of the foregoing, x is 0 and y is 1 and the carrier peptide comprises the sequence (R ^d R ^d Y ^b ) _z . In another embodiment, n is 5 and Y ^b is an aminohexanoic acid moiety. In another embodiment, n is 2 and Y ^b is a β-alanine moiety. In another embodiment, R ^e is hydrogen.

In another embodiment, the carrier peptide comprises the sequence (R ^d Y ^b ) _p , wherein R ^d and Y ^b are as defined above and p is an integer ranging from 2 to 8. In other embodiments, each R ^d is arginine. In another embodiment, n is 5 and Y ^b is an aminohexanoic acid moiety. In another embodiment, n is 2 and Y ^b is a β-alanine moiety. In another embodiment, R ^e is hydrogen.

In another embodiment, the carrier peptide comprises the sequence ILFQY. The peptide may comprise an ILFQY sequence in addition to any of the other sequences described herein. For example, the carrier peptide can be ILFQY and [(R ^d Y ^b R ^d ) _x (R ^d R ^d Y ^b ) _y ] _z , [(R ^d R ^d Y ^b ) _y (R ^d Y ^b R ^d ) _x ] _z , (R ^d Y ^b ) _p or a combination thereof, wherein R ^d , x, y and Y ^b are as defined above. [(R ^d Y ^b R ^d ) _x (R ^d R ^d Y ^b ) _y ] _z , [(R ^d R ^d Y ^b ) _y (R ^d Y ^b R ^d ) _x ] _z or (R ^d Y ^b ) _{The p} sequence may be at the amino terminus, the carboxy terminus, or both of the ILFQY sequence. In certain embodiments, x is 1 and y is 0 and the carrier peptide comprises (R ^d Y ^b R ^d ) _z linked to the ILFQY sequence via an optional Z linker.

In other related embodiments, the carrier peptide comprises the sequence ILFQ, IWFQ or ILIQ. Another embodiment comprises a carrier peptide comprising the sequence PPMWS, PPMWT, PPMFS or PPMYS. The carrier peptide may be, for example, the sequence [(R ^d Y ^b R ^d ) _x (R ^d R ^d Y ^b ) _y ] _z , [(R ^d R ^d Y ^b ) _y (R ^d Y ^b R ^d ) _x ] _z or (R ^d Y ^b ) _p , wherein R ^d , x, y and Y ^b are as defined above.

Some embodiments of carrier peptides include modifications to naturally occurring amino acid subunits, eg, the amino acid terminus or carboxy terminus amino acid subunits may be modified. Such modifications include capping free amino or free carboxy with hydrophobic groups. For example, the amino terminus may be capped with an acetyl, benzoyl or stearyl moiety. For example, any of the peptide sequences in Table 1 may have such modifications, even if not specifically indicated in the table. In these embodiments, the amino terminus of the carrier peptide can be represented as:

또는

or

In another embodiment, the carrier peptide comprises at least one of alanine, asparagine, cysteine, glutamine, glycine, histidine, lysine, methionine, serine or threonine.

In some of the embodiments described herein, the carrier peptide consists of the described sequence and a carboxy terminal glycine or proline amino acid subunit.

In some embodiments, the carrier peptide has the following sequence (amino terminus to carboxy terminus): R ₆ G, R ₇ G, R ₈ G, R ₅ GR ₄ G, R ₅ F ₂ R ₄ G, Tat-G, rTat It does not consist of -G, (RXR ₂ G ₂ ) ₂ or (RXR ₃ X) _{2 G.} In another embodiment, the carrier peptide does not consist _{of R 8} G, R ₉ G or R ₉ F _{2 G.} In yet other embodiments, the carrier peptide is Tat-G, rTat-G, R ₉ F ₂ G, R ₅ F ₂ R ₄ , R ₄ G, R ₅ G, R ₆ G, R ₇ G, R ₈ G , R ₉ G, (RXR) ₄ G, (RXR) ₅ G, (RXRRBR) ₂ G, (RAR) ₄ F ₂ or (RGR) ₄ F ₂ . In other embodiments, the carrier peptide does not consist of _{“Penetratin” or “R 2 Pen”.}

In another aspect, the present invention provides peptide-nucleic acid analog conjugates, a nucleic acid analog having a substantially uncharged backbone and a targeting sequence, and a carboxy terminal glycine or proline amino acid subunit covalently linked to the nucleic acid analog. and 8 to 16 additional other subunits selected from ^{R d subunits, Y subunits, and optional Z subunits, wherein the peptide comprises at least 8 R d} subunits, at least 2 Y subunits and at most 3 Z subunits. including,

wherein >50% of the subunits are R ^d subunits,

(a) each R ^d subunit independently represents arginine or an arginine analog, wherein the arginine analog is a cationic α-amino acid comprising a side chain ^{of the formula R a} N=C(NH ₂ )R ^{b , wherein R a} is H or R ^c ; R ^b is R ^c , NH ₂ , NHR, or N(R ^c ) ₂ , wherein R ^c is lower alkyl or lower alkenyl and optionally also ^{includes nitrogen or R a} or R ^b are taken together to form a ring. Also, the side chain is linked to an amino acid through ^{R a} or R ^{b ;}

(b) said at least two Y subunits are Y ^a or Y ^b , wherein:

(i) each Y ^a is independently a neutral α-amino acid subunit having a side chain independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and aralkyl, wherein the side chain is a substituted When selected from alkyl, alkenyl and alkynyl, it contains at most one heteroatom every 2 carbon atoms, preferably every 4 carbon atoms, and more preferably every 6 carbon atoms, wherein said subunits are adjacent or flanking the linker site, and also

(ii) Y ^b is

is,

wherein n is 2 to 7 and each R ^e at each occurrence is independently hydrogen or methyl, and

(c) Z is alanine, asparagine, cysteine, glutamine, glycine, histidine, lysine, methionine, serine, threonine and naturally occurring side chains excluding negatively charged side chains (e.g., carboxylate side chains) at physiological pH Represents an amino acid subunit selected from amino acids that are one or two carbon homologues of a side chain. In some embodiments, the side chain is neutral. In other embodiments, the Z side chain is a side chain of a naturally occurring amino acid. In some embodiments the optional Z subunit is selected from alanine, glycine, methionine, serine, and threonine. The carrier peptide may comprise 0, 1, 2, or 3 Z subunits, and in some embodiments at most 2 Z subunits.

In selected embodiments, the carrier peptide has ^{two Y subunits of precisely type Y a} , which are contiguous or flank cysteine subunits. In some embodiments, two Y ^a subunits are adjacent. In another embodiment, ^{the side chain of the Y a} subunit comprises side chains of naturally occurring amino acids or one and two carbon analogs thereof, excluding charged side chains at physiological pH. Another possible side chain is that of a naturally occurring amino acid. In a further embodiment, the side chain is an aryl or aralkyl side chain, eg, each Y ^a is independently selected from phenylalanine, tyrosine, tryptophan, leucine, isoleucine and valine.

In selected embodiments, each Y ^a is independently selected from phenylalanine and tyrosine. In a further embodiment, each Y ^a is phenylalanine. This includes, for example, a conjugate consisting of an arginine subunit, a phenylalanine subunit, a glycine or proline amino acid subunit, an optional linker moiety, and a nucleic acid analog. One such conjugate includes _{a peptide having the formula Arg 9} Phe ₂ aa, wherein aa is glycine or proline.

The aforementioned carrier peptides may also include ILFQY, ILFQ, IWFQ or ILIQ. Other embodiments include the aforementioned carrier peptides comprising the sequence PPMWS, PPMWT, PPMFS or PPMYS.

The peptide-oligomer conjugate of the present invention inhibits the expression of target mRNA in a protein expression system including a cell-free translation system; inhibit splicing of target pre-mRNA; It is also more effective than unconjugated oligomers in a variety of functions, including inhibiting viral replication, which regulates viral nucleic acid replication or mRNA transcription.

Also included within the scope of the present invention are conjugates of other pharmacological agents (ie not nucleic acid analogs) and carrier peptides. Specifically, some embodiments

(a) a carrier peptide comprising an amino acid subunit; and

(b) pharmacological agents

It provides a conjugate comprising;

here:

At least two of the amino acid subunits are positively charged amino acids, and the carrier peptide comprises a glycine (G) or proline (P) amino acid subunit at the carboxy terminus of the carrier peptide, and the carrier peptide is covalently attached to the pharmacological agent. The carrier peptide in these embodiments may be any of the carrier peptides described herein. Also provided are methods of delivering a pharmacological agent by conjugating the pharmacological agent to a carrier peptide.

Although the pharmacological agent to be supplied may be a compound used for detection such as a fluorescent compound, it may be a physiologically active agent, for example, a therapeutic or prophylactic agent. Physiologically active agents include drugs selected from biomolecules, such as peptides, proteins, saccharides, or nucleic acids, in particular antisense oligonucleotides, or “small molecule” organic or inorganic compounds. A “small molecule” compound may be broadly defined as an organic, inorganic, or organometallic compound that is not a biomolecule as described above. Typically, such compounds have a molecular weight of less than 1000, or in some embodiments less than 500.

In one embodiment, the pharmacological agent to be delivered does not comprise a single amino acid, dipeptide, or tripeptide. In another embodiment, no short oligopeptides are included, ie the oligopeptides have less than 6 amino acid subunits. In a further embodiment no longer oligopeptides are included, ie the oligopeptides have 7 to 20 amino acid subunits. In a further embodiment, no polypeptides, or proteins, having 20 or more amino acid subunits are included.

Carrier peptides are effective in increasing transport of a pharmacological agent into cells relative to a pharmacological agent conjugated to a corresponding peptide lacking the glycine or proline subunit, compared to a pharmacological agent having less toxicity and/or an unconjugated form. . In some embodiments, transport is increased by at least 2, at least 5 or at least 10 factors. In other embodiments, toxicity is reduced (ie, maximally tolerated dose is increased) by at least 2, at least 5, or at least 10 factors.

A. Peptide Linkers

The carrier peptide can be linked to the agent to be delivered (eg, a nucleic acid analog, a pharmacological agent, etc.) by a variety of methods available to those skilled in the art. In some embodiments, the carrier peptide is linked directly to the nucleic acid analog without an interfering linker. In this regard, the formation of an amide bond between the free amine of the free carboxy and the terminal amino acid on a nucleic acid analog may be useful to form a conjugate. In certain embodiments, the carboxy terminal glycine or proline subunit is linked directly to the 3' end of the nucleic acid analog. For example, a carrier peptide can be linked by forming an amide bond between the carboxy terminal glycine or proline moiety and the 3' morpholino ring nitrogen (see, eg, Figure 1C).

In some embodiments, the nucleic acid analog is ^{conjugated to the carrier via a linker moiety selected from a} Y a or Y ^b subunit, a cysteine subunit, and an uncharged, non-amino acid linker moiety. In other embodiments, the nucleic acid analog is linked to the carrier peptide directly via a glycine or proline at the 5' or 3' end of the nucleic acid analog. In some embodiments, the carrier peptide is linked directly to the 3' of the nucleic acid analog via a glycine or proline amino acid subunit, eg, to the 3' morpholino nitrogen via an amide bond.

In another embodiment, the conjugate comprises a binding moiety between the terminal glycine or proline amino acid subunits. In some of the embodiments, the linker is selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate and phosphodiester. Up to 18 atoms in length, including bonds. In certain embodiments, the linker comprises phosphorodiamidate and piperazine linkages. For example, in some embodiments the linker has the formula (XXIX):

wherein R ²⁴ is absent or is H or C ₁ -C ₆ alkyl. In certain embodiments, R ²⁴ is absent and in other embodiments Formula (XXIX) links the 5' end of the nucleic acid analog (eg, morpholino oligomer) to the carrier peptide (see eg FIG. 1B ). .

In some embodiments, ^{the side chain portion of the R d} subunit is independently guanidyl (HN=C(NH ₂ )NH-), amidinyl (HN=C(NH ₂ )C<), 2-aminodihydropyridyl , 2-aminotetrahydropyrimidyl, 2-aminopyridinyl and 2-amino pyrimidinyl.

In some embodiments, ^{the side chain portion of the R d} subunit is independently guanidyl (HN=C(NH ₂ )NH-), amidinyl (HN=C(NH ₂ )C<), 2-aminodihydroxy pyrimidyl, 2-aminotetrahydroxypyrimidyl, 2-aminopyridinyl and 2-amino pyrimidinyl.

Multiple carrier peptides may be attached to a single compound as desired, alternatively, multiple compounds may be conjugated to a single transporter. The linker between the carrier peptide and the nucleic acid analog may also consist of a natural or unnatural amino acid (eg, 6-aminohexanoic acid or β-alanine). Such linkers may also be formed between the amine or hydroxyl group of the nucleic acid analog (eg at the 3' morpholino nitrogen or 5' OH) formed by condensation catalyzed, for example, by a carbodiimide and between the carboxy terminus of the transporter peptide. Direct bonding may be involved.

In general, the linker may include any non-reactive moiety that does not interfere with transport or function of the conjugate. Linkers can be selected from those that do not cleav under normal conditions of use, such as those containing, for example, ether, thioether, amide, or carbamate linkages. In other embodiments, it may be desirable to include a linkage between a carrier peptide capable of being cleaved in vivo and a compound (eg, an oligonucleotide analog, a pharmacological agent, etc.). Bonds that can be cleaved in vivo are known in the art and also include, for example, enzymatically hydrolyzed carboxylic acid esters, and disulfides that are cleaved in the presence of glutathione. It may also be feasible to cleave photolytically cleavable bonds such as ortho-nitrophenyl ethers in vivo by applying radiation of an appropriate wavelength. Exemplary heterobifunctional binders further comprising a cleavable disulfide group include N-hydroxysuccinimidyl 3-[(4-azidophenyl)dithio]propionate and Vanin, E.F. and others described in Ji, T.H., Biochemistry 20:6754-6760 (1981).

C. Exemplary Carrier Peptides

A table of exemplary carrier peptide and oligonucleotide sequences is provided in Table 1 below. In some embodiments, the present invention provides a peptide oligomer, wherein the peptide comprises or consists of any one of the peptide sequences in Table 1. In another embodiment, the nucleic acid analog comprises or consists of any of the oligonucleotides in Table 1f. In yet another embodiment, the present invention provides a peptide oligomer, wherein the peptide comprises or consists of any of the peptide sequences in Table 1, and wherein the nucleic acid comprises or consists of any of the oligonucleotides in Table 1 is composed of In another embodiment, the present invention provides a peptide comprising or consisting of any one of the sequences in Table 1.

Table 1. Exemplary carrier peptide and oligonucleotide sequences

aa = glycine or proline; B = β-alanine; X = 6-aminohexanoic acid; tg = unmodified amino terminus, or amino terminus capped with acetyl, benzoyl or stearoyl groups (ie acetyl amide, benzoyl amide or stearoyl amide) and Y ^b is of the formula -C(O)-(CHR ^e ) _n - NH—, wherein 2 to 7 and each R ^e at each occurrence is independently hydrogen or methyl. Briefly, not all sequences are noted with terminal tg groups. However, each of the above sequences may comprise an unmodified aminoterminus or an aminoterminus capped with an acetyl, benzoyl or stearoyl group.

III. antisense oligomer

Nucleic acid analogs included in the conjugates of the present invention are substantially uncharged synthetic oligomers capable of base-specific binding to a target sequence of a polynucleotide, for example, an antisense oligonucleotide analog. Such analogs include, for example, methylphosphonates, peptide nucleic acids, substantially uncharged N3′→5′ phosphoramidates and morpholino oligomers.

The base sequence of a nucleic acid analog provided as a base pair supported by an analog backbone is A, T, C, G and U bases or non-stranded inosine (I) and 7-deaza- It can be any sequence comprising a G base.

In some embodiments, the nucleic acid analog is a morpholino oligomer, i.e., an oligonucleotide analog composed of morpholino subunits of the form shown in Figure 1, wherein (i) the structure is one at the 5' exocyclic carbon of the adjacent subunit. are linked together by phosphorus-containing bonds of 1 to 3 atoms long, preferably 2 atoms long, which bind the subunits of the morpholino nitrogen, and (ii) Pi and Pj are involved in base specific hydrogen bonding. Thus, it is a purine or pyrimidine base pairing moiety effective for linking to a base in a polynucleotide. The purine or pyrimidine base pair moiety is typically adenyl, cytosine, guanine, uracil or thymine. The synthesis, structure, and binding properties of morpholino oligomers are described further below and are also described in detail in US Pat. Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,521,063 and 5,506,337. described, all of which are incorporated herein by reference.

Desirable chemical properties of morpholino-based oligomers include their ability to selectively hybridize using complementary base target nucleic acids comprising target RNAs with high Tm, even using short oligomers of 8-14 bases, mammalian including the ability of an oligomeric:RNA heteroduplex to actively transport intracellularly, and to resist RNAse degradation.

In a preferred embodiment, the morpholino oligomer is about 8-10 subunits in length. More preferably, the oligomer is about 8-20, about 8-16, about 10-30, or about 12-25 subunits in length. For some applications, such as antimicrobials, short oligomers, eg about 8-12 subunits in length, may be particularly advantageous when attached to a peptide transporter as described herein.

A. Oligomers with Modified Intersubunit Linkers

One embodiment of the invention relates to peptide-oligomeric conjugates comprising a nucleic acid analog (eg, a morpholino oligomer) comprising a linkage between modified subunits. In some embodiments, the conjugate has a higher affinity for DNA and RNA than in the corresponding unmodified oligomer, and also exhibits improved cell delivery, efficacy, and/or tissue distribution properties compared to an oligomer having other intersubunit linkages. prove it In one embodiment, the conjugate comprises one or more intersubunit linkages of type (A) as defined below. In another embodiment, the conjugate comprises one or more intersubunit linkages of type (B) as defined below. In still other embodiments, the conjugate comprises intersubunit linkages of type (A) and type (B) as described in more detail below. In another embodiment, the conjugate comprises a morpholino oligomer as detailed below. The structural features and properties of the various linkage types and oligomers are described in more detail in the discussion that follows.

1. Combine (A)

Applicants have discovered that increases in antisense activity, biodispersion and/or other desirable properties can be optimized by preparing oligomers with various intermolecular linkages. For example, the oligomer optionally comprises one or more intermolecular linkages of type (A) and in certain embodiments the oligomer comprises at least one linkage of type (A), e.g., each linkage is It may be of type (A). In some embodiments, each type (A) bond has the same structure. Type (A) linkages include those described in shared U.S. Patent No. 7,943,762, which is incorporated herein by reference in its entirety. Bond (A) has the following formula (I): or a salt or isomer thereof, wherein 3' and 5' represent the point of attachment to 3' and 5' of the morpholino ring, respectively (i.e. the formula (I) discussed below I)):

In the above formula,

W at each occurrence is independently S or O;

X at each occurrence is independently —N(CH ₃ ) ₂ , —NR ¹ R ² , —OR ³ or formula (II)

;

Y at each occurrence is independently O or —NR ² ;

R ¹ at each occurrence is independently hydrogen or methyl;

R ² at each occurrence is independently hydrogen or —LNR ⁴ R ⁵ R ⁷ ;

R ³ at each occurrence is independently hydrogen or C ₁ -C ₆ alkyl;

R ⁴ at each occurrence is independently hydrogen, methyl, -C(=NH)NH ₂ , -ZL-NHC(=NH)NH ₂ or -[C(=O)CHR'NH] _m H, wherein Z is -C(=O)- or a direct bond, R' is a side chain of a naturally occurring amino acid or one or two carbon analogs thereof, and m is 1 to 6;

R ⁵ at each occurrence is independently hydrogen, methyl or an electron pair;

R ⁶ at each occurrence is independently hydrogen or methyl;

R ⁷ at each occurrence is independently hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxyalkyl;

L is an optional linker of up to 18 atoms in length comprising an alkyl, alkoxy or alkylamino group or a combination thereof.

In some embodiments, the oligomer comprises at least one type (A) linkage. In some other embodiments, the oligomer comprises at least two consecutive type (A) linkages. In a further embodiment, at least 5% of the linkages in the oligomer are of type (A); For example, in some embodiments, 5%-95%, 10% to 90%, 10% to 50%, or 10% to 35% of the binding may be of type (A) binding. In some specific embodiments, at least one type (A) bond is —N(CH ₃ ) ₂ , and in still other embodiments each bond in the oligomer is —N(CH ₃ ) ₂ . In other embodiments, at least one type (A) linkage is piperizin-1-yl, eg, unsubstituted piperazin-1-yl (eg, A2 or A3). In another embodiment, each type (A) linkage is piperizin-1-yl, eg, unsubstituted piperazin-1-yl.

In some embodiments, at each occurrence, W is independently S or O, and in certain embodiments, W is O.

In some embodiments, at each occurrence, X is independently —N(CH ₃ ) ₂ , —NR ¹ R ² , —OR ³ . In some embodiments, X is —N(CH ₃ ) ₂ . In another aspect X is —NR ¹ R ² , and in another embodiment X is —OR ³ .

In some embodiments, R ¹ at each occurrence is independently hydrogen or methyl. In some embodiments, R ¹ is hydrogen. In another embodiment X is methyl.

In some embodiments, R ² at each occurrence is independently hydrogen. In other embodiments, R ² at each occurrence is -LNR ⁴ R ⁵ R ⁷ . In some embodiments, R ³ at each occurrence is independently hydrogen or C ₁ -C ₆ alkyl. In other embodiments, R ³ is methyl. In another embodiment, R ³ is ethyl. In some other embodiments, R ³ is n-propyl or isopropyl. In some other embodiments, R ³ is C ₄ alkyl. In other embodiments, R ³ is C ₅ alkyl. In some embodiments R ³ is C ₆ alkyl.

In certain embodiments, R ⁴ at each occurrence is independently hydrogen. In other embodiments, R ⁴ is methyl. In still other embodiments, R ⁴ is —C(=NH)NH ₂ , and in yet other embodiments R ⁴ is —ZL-NHC(=NH)NH ₂ . In still other embodiments, R ⁴ is -[C(=O)CHR'NH] _m H. Z is -C(=O)- in one embodiment and Z is a direct bond in another embodiment. R' is the side chain of a naturally occurring amino acid. In some embodiments, R′ is a one or two carbon homologue of a side chain of a naturally occurring amino acid.

m is an integer from 1 to 6. m may be 1. m may be 2. m may be 3. m may be 4. m may be 5. m may be 6.

In some embodiments, R ⁵ at each occurrence is independently hydrogen, methyl, or an electron pair. In some embodiments, R ⁵ is hydrogen. In other embodiments, R ⁵ is methyl. In still other embodiments, R ⁵ is an electron pair.

In some embodiments, R ⁶ at each occurrence is independently hydrogen or methyl. In some embodiments, R ⁶ is hydrogen. In other embodiments, R ⁶ is methyl.

In other embodiments, R ⁷ at each occurrence is independently hydrogen C ₁ -C ₆ alkyl or C ₂ -C ₆ alkoxyalkyl. In some embodiments, R ⁷ is hydrogen. In other embodiments, R ⁷ is C ₁ -C ₆ alkyl. In another embodiment, R ⁷ is C ₂ -C ₆ alkoxyalkyl. In some embodiments, R ⁷ is methyl. In other embodiments, R ⁷ is ethyl. In still other embodiments, R ⁷ is n-propyl or isopropyl. In some other embodiments, R ⁷ is C ₄ alkyl. In some embodiments, R ⁷ is C ₅ alkyl. In some embodiments, R ⁷ is C ₆ alkyl. In yet another embodiment, R ⁷ is C ₂ alkoxyalkyl. In some other embodiments, R ⁷ is C ₃ alkoxyalkyl. In still other embodiments, R ⁷ is C ₄ alkoxyalkyl. In some embodiments, R ⁷ is C ₅ alkoxyalkyl. In other embodiments, R ⁷ is C ₆ alkoxyalkyl.

A linker group L, as indicated above, forms a bond in its backbone selected from _{alkyl (eg -CH 2} -CH ₂ -), alkoxy (eg -COC-), and alkylamino (eg -CH _{2 -NH-).} with the proviso that the terminal atom in L (eg, carbonyl or those adjacent to nitrogen) is a carbon atom. Linkers are generally unbranched, although branching bonds (eg -CH ₂ -CHCH _{3 -) are possible.} In one embodiment, the linker is a hydrocarbon linker. Such linkers may have the formula (CH ₂ ) _n —, where n is 1 to 12, preferably 2 to 8, and more preferably 2 to 6.

Oligomers having any number of linkage types (A) are provided. In some embodiments, the oligomer contains no linkages of type (A). In certain embodiments, 5, 10, 20, 30, 40, 50, 60, 70, 80 or 90 percent of the bonds are (A). In selected embodiments, 10 to 80, 20 to 80, 20 to 60, 20 to 50, 20 to 40, or 20 to 35 percent of the bonds are (A). In still other embodiments, each bond is of type (A).

2. Combine (B)

In some embodiments, the oligomer comprises at least one type (A) linkage. For example, the oligomer may contain 1, 2, 3, 4, 5, 6 or more type (B) linkages. Type (B) linkages may be contiguous or may be located through an oligomer. Bond type (B) has the following formula (I): or a salt or isomer thereof:

In the above formula,

W at each occurrence is independently S or O;

X at each occurrence is independently —NR ⁸ R ⁹ or —OR ³ ; Also

Y at each occurrence is independently O or -NR ¹⁰ ,

R ³ at each occurrence is independently hydrogen or C ₁ -C ₆ alkyl;

R ⁸ is, at each occurrence, independently hydrogen or C ₂ -C ₁₂ alkyl;

R ⁹ at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ aralkyl or aryl;

R ¹⁰ at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, or —LNR ⁴ R ⁵ R ⁷ ;

wherein R ⁸ and R ⁹ may be joined to form a 5 to 18 membered mono or bicyclic heterocycle or R ⁸ , R ⁹ or R ³ may be taken ^{together with R 10} to form a 5 to 7 membered heterocycle Also, X is 4-piperazino and X has the formula (III):

In the above formula,

R ¹¹ at each occurrence is independently C ₂ -C ₁₂ alkyl, C ₁ -C ₁₂ aminoalkyl, C ₁ -C ₁₂ alkylcarbonyl, aryl, heteroaryl, or heterocyclyl;

R at each occurrence is independently an electron pair, hydrogen or C ₁ -C ₁₂ alkyl; Also

R ¹² at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ aminoalkyl, —NH ₂ , —CONH ₂ , —NR ¹³ R ¹⁴ , —NR ¹³ R ¹⁴ R ¹⁵ , C ₁ -C ₁₂ alkylcarbonyl, oxo, -CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl , cholate, deoxycholate, aryl, heteroaryl, heterocycle, -SR ¹³ or C ₁ -C ₁₂ alkoxy, and R ¹³ , R ¹⁴ and R ¹⁵ at each occurrence are independently C ₁ -C ₁₂ alkyl.

In some instances, the oligomer comprises one linkage of type (B). In some other embodiments, the oligomer comprises two linkages of type (B). In some other embodiments, the oligomer comprises three linkages of type (B). In some other embodiments, the oligomer comprises linkages of type (B). In still other embodiments, the bonds of type (B) are continuous (ie, bonds of type (B) are adjacent to each other). In a further embodiment, at least 5% of the linkages in the oligomer are of type (B). For example, in some embodiments, 5% to 95%, 10% to 90%, 10% to 50%, or 10% to 35% of the bonds may be of type (B) binding.

In other embodiments, R ³ at each occurrence is independently hydrogen or C ₁ -C ₆ alkyl. In still other embodiments, R ³ can be methyl. In some embodiments, R ³ can be ethyl. In some other embodiments, R ³ can be n-propyl or isopropyl. In still other embodiments, R ³ can be C _{4 alkyl.} In some embodiments, R ³ can be C _{5 alkyl.} In some embodiments, R ³ can be C _{6 alkyl.}

In some embodiments, R ⁸ at each occurrence is independently hydrogen or C ₂ -C ₁₂ alkyl. In some embodiments, R ⁸ is hydrogen. In yet other embodiments, R ⁸ is ethyl. In some other embodiments, R ⁸ is n-propyl or isopropyl. In some embodiments, R ⁸ is C ₄ alkyl. In yet other embodiments, R ⁸ is C ₅ alkyl. In other embodiments, R ⁸ is C ₆ alkyl. In some embodiments, R ⁸ is C ₇ alkyl. In yet other embodiments, R ⁸ is C ₈ alkyl. In other embodiments, R ⁸ is C ₉ alkyl. In yet other embodiments, R ⁸ is C ₁₀ alkyl. In some embodiments, R ⁸ is C ₁₁ alkyl. In yet other embodiments, R ⁸ is C ₁₂ alkyl. In some other embodiments R ⁸ is C ₂ -C ₁₂ alkyl and wherein said C ₂ -C ₁₂ alkyl includes one or more double bonds (eg, alkene), triple bonds (eg, alkyne), or both. In some embodiments, R ⁸ is unsubstituted C ₂ -C ₁₂ alkyl.

In some embodiments, R ⁹ at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ aralkyl, or aryl. In some embodiments, R ⁹ is hydrogen. In yet other embodiments, R ⁹ is C ₁ -C ₁₂ alkyl. In other embodiments, R ⁹ is methyl. In yet other embodiments, R ⁹ is ethyl. In some embodiments, R ⁹ is n-propyl or isopropyl. In some embodiments, R ⁹ is C ₄ alkyl. In some embodiments, R ⁹ is C ₅ alkyl. In yet other embodiments, R ⁹ is C ₆ alkyl. In some embodiments, R ⁹ is C ₇ alkyl. In some embodiments, R ⁹ is C ₈ alkyl. In some embodiments, R ⁹ is C ₉ alkyl. In some embodiments, R ⁹ is C ₁₀ alkyl. In some embodiments, R ⁹ is C ₁₁ alkyl. In yet other embodiments, R ⁹ is C ₁₂ alkyl.

In some other embodiments, R ⁹ is C ₁ -C ₁₂ aralkyl. For example, in some embodiments R ⁹ is benzyl wherein the benzyl may be optionally substituted on a phenyl ring or on a benzyl carbon. Substituents in this context include alkyl and alkoxy groups such as methyl or methoxy. In some embodiments, the benzyl group is substituted with methyl at the benzyl carbon. For example, in some embodiments, R ⁹ has Formula (XIV):

In other embodiments, R ⁹ is aryl. For example, in some embodiments R ⁹ is phenyl, which phenyl may be optionally substituted. Substituents in this context include alkyl and alkoxy groups such as methyl or methoxy. In other embodiments, R ⁹ is phenyl, wherein the phenyl comprises a crown ether moiety, for example a 12-18 membered crown ether. In one embodiment the crown ether is 18 membered and may further comprise an additional phenyl moiety. For example in one embodiment R ⁹ has one of the following formulas (XV) or (XVI):

또는

or

In some embodiments, R ¹⁰ at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, or -LNR ⁴ R ⁵ R ⁷ , wherein R ⁴ , R ⁵ and R ⁷ are defined above for bond (A). same as it has been In other embodiments, R ¹⁰ is hydrogen. In other embodiments, R ¹⁰ is C ₁ -C ₁₂ alkyl, and in other embodiments R ¹⁰ is -LNR ⁴ R ⁵ R ⁷ . In some embodiments, R ¹⁰ is methyl. In yet other embodiments, R ¹⁰ is ethyl. In some embodiments, R ¹⁰ is C ₃ alkyl. In some embodiments, R ¹⁰ is C ₄ alkyl. In yet other embodiments, R ¹⁰ is C ₅ alkyl. In some other embodiments, R ¹⁰ is C ₆ alkyl. In other embodiments R ¹⁰ is C ₇ alkyl. In yet other embodiments, R ¹⁰ is C ₈ alkyl. In some embodiments, R ¹⁰ is C ₉ alkyl. In other embodiments, R ¹⁰ is C ₁₀ alkyl. In yet other embodiments, R ¹⁰ is C ₁₁ alkyl. In some other embodiments, R ¹⁰ is C ₁₂ alkyl.

In some embodiments, R ⁸ and R ⁹ are joined to form a 5-18 membered mono or bicyclic heterocycle. In some embodiments the heterocycle is a 5 or 6 membered monocyclic heterocycle. For example, in some embodiments, bond (B) has formula (IV):

In the above formula,

Z represents a 5 or 6 membered monocyclic heterocycle.

In other embodiments, the heterocycle is bicyclic, eg, a 12-membered bicyclic heterocycle. The heterocycle may be piperizinyl. The heterocycle may be morpholino. The heterocycle may be piperidinyl. The heterocycle may be decahydroisoquinoline. Representative heterocycles include the formula:

In some embodiments, R ¹¹ at each occurrence is independently C ₂ -C ₁₂ alkyll, C ₁ -C ₁₂ aminoalkyl, aryl, heteroaryl, or heterocyclyl.

In some embodiments, R ¹¹ is C ₂ -C ₁₂ alkyl. In some embodiments, R ¹¹ is ethyl. In other embodiments, R ¹¹ is C ₃ alkyl. In yet other embodiments, R ¹¹ is isopropyl. In some other embodiments, R ¹¹ is C ₄ alkyl. In other embodiments, R ¹¹ is C ₅ alkyl. In some embodiments, R ¹¹ is C ₆ alkyl. In other embodiments, R ¹¹ is C ₇ alkyl. In some embodiments, R ¹¹ is C ₈ alkyl. In other embodiments, R ¹¹ is C ₉ alkyl. In yet other embodiments, R ¹¹ is C ₁₀ alkyl. In some other embodiments, R ¹¹ is C ₁₁ alkyl. In some embodiments, R ¹¹ is C ₁₂ alkyl.

In other embodiments, R ¹¹ is C ₁ -C ₁₂ aminoalkyl. In some embodiments, R ¹¹ is methylamino. In some embodiments, R ¹¹ is ethylamino. In other embodiments, R ¹¹ is C ₃ aminoalkyl. In yet other embodiments, R ¹¹ is C ₄ aminoalkyl. In some other embodiments, R ¹¹ is C ₅ aminoalkyl. In other embodiments, R ¹¹ is C ₆ aminoalkyl. In yet other embodiments, R ¹¹ is C ₇ aminoalkyl. In some embodiments, R ¹¹ is C ₈ aminoalkyl. In other embodiments, R ¹¹ is C ₉ aminoalkyl. In yet other embodiments, R ¹¹ is C ₁₀ aminoalkyl. In some other embodiments, R ¹¹ is C ₁₁ aminoalkyl. In other embodiments R ¹¹ is C ₁₂ aminoalkyl.

In other embodiments, R ¹¹ is C ₁ -C ₁₂ alkylcarbonyl. In yet other embodiments, R ¹¹ is C ₁ alkylcarbonyl. In other embodiments, R ¹¹ is C ₂ alkylcarbonyl. In some embodiments, R ¹¹ is C ₃ alkylcarbonyl. In yet other embodiments, R ¹¹ is C ₄ alkylcarbonyl. In some embodiments, R ¹¹ is C ₅ alkylcarbonyl. In some embodiments, R ¹¹ is C ₆ alkylcarbonyl. In other embodiments, R ¹¹ is C ₇ alkylcarbonyl. In yet other embodiments, R ¹¹ is C ₈ alkylcarbonyl. In some embodiments, R ¹¹ is C ₉ alkylcarbonyl. In yet other embodiments, R ¹¹ is C ₁₀ alkylcarbonyl. In some other embodiments, R ¹¹ is C ₁₁ alkylcarbonyl. In some embodiments, R ¹¹ is C ₁₂ alkylcarbonyl. In yet other embodiments, R ¹¹ is —C(=O)(CH ₂ ) _n CO ₂ H, wherein n is 1-6. For example, in some embodiments, n is 1. In another embodiment n is 2. In still other embodiments, n is 3. In some other embodiments, n is 4. In still other embodiments, n is 5. In another embodiment, n is 6.

In other embodiments, R ¹¹ is aryl. For example, in some embodiments, R ¹¹ is phenyl. In some embodiments, the phenyl is substituted with, for example, a nitro group.

In other embodiments, R ¹¹ is heteroaryl. For example, in some embodiments, R ¹¹ is pyridinyl. In other embodiments, R ¹¹ is pyrimidinyl.

In other embodiments, R ¹¹ is heterocyclyl. For example, in some embodiments, R ¹¹ is piperidinyl, eg, piperidin-4-yl.

In some embodiments, R ¹¹ is ethyl, isopropyl, piperidinyl, pyrimidinyl, cholate, deoxycholate, or —C(=O)(CH ₂ ) _n CO ₂ H, wherein n is 1 to 6 to be.

In some embodiments, R is an electron pair. In other embodiments, R is hydrogen and in embodiments R is C ₁ -C ₁₂ alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In other embodiments, R is C ₃ alkyl. In still other embodiments, R is isopropyl. In some other embodiments, R is C ₄ alkyl. In yet other embodiments, R is C ₅ alkyl. In some embodiments, R is C ₆ alkyl. In other embodiments, R is C ₇ alkyl. In yet other embodiments, R is C ₈ alkyl. In other embodiments, R is C ₉ alkyl. In some embodiments, R is C ₁₀ alkyl. In yet other embodiments, R is C ₁₁ alkyl. In some embodiments, R is C ₁₂ alkyl.

In some embodiments, R ¹² at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ aminoalkyl, —NH ₂ , —CONH ₂ , —NR ¹³ R ¹⁴ , —NR ¹³ R ^{14 .} R ¹⁵ , oxo, -CN, trifluoromethyl, amidyl, amidinyl, amidinylalkyl, amidinylalkylcarbonyl guanidinyl, guanidinylalkyl, guanidinylalkylcarbonyl, cholate, de oxycholate, aryl, heteroaryl, heterocycle, —SR ¹³ or C ₁ -C ₁₂ alkoxy, wherein R ¹³ , R ¹⁴ and R ¹⁵ at each occurrence independently include C ₁ -C ₁₂ alkyl.

In some embodiments, R ¹² is hydrogen. In some embodiments, R ¹² is C ₁ -C ₁₂ alkyl. In some embodiments, R ¹² is C ₁ -C ₁₂ aminoalkyl. In some embodiments, R ¹² is —NH ₂ . In some embodiments, R ¹² is —CONH ₂ . In some embodiments, R ¹² is —NR ¹³ R ¹⁴ . In some embodiments, R ¹² is —NR ¹³ R ¹⁴ R ¹⁵ . In some embodiments, R ¹² is C ₁ -C ₁₂ alkylcarbonyl. In some embodiments, R ¹² is oxo. In some embodiments, R ¹² is —CN. In some embodiments, R ¹² is trifluoromethyl. In some embodiments, R ¹² is amidyl. In some embodiments, R ¹² is amidinyl. In some embodiments, R ¹² is amidinylalkyl. In some embodiments, R ¹² is amidinylalkylcarbonyl. In some embodiments, R ¹² is guanidinyl, for example mono methylguanidinyl or dimethylguanidinyl. In some embodiments, R ¹² is guanidinylalkyl. In some embodiments, R ¹² is amidinylalkylcarbonyl. In some embodiments, R ¹² is cholate. In some embodiments, R ¹² is deoxycholate. In some embodiments, R ¹² is aryl. In some embodiments, R ¹² is heteroaryl. In some embodiments, R ¹² is heterocycle. In some embodiments, R ¹² is —SR ¹³ . In some embodiments, R ¹² is C ₁ -C ₁₂ alkoxy. In some embodiments, R ¹² is dimethyl amine.

In other embodiments, R ¹² is methyl. In still other embodiments, R ¹² is ethyl. In some embodiments, R ¹² is C ₃ alkyl. In some embodiments, R ¹² is isopropyl. In some embodiments, R ¹² is C ₄ alkyl. In other embodiments, R ¹² is C ₅ alkyl. In yet other embodiments, R ¹² is C ₆ alkyl. In some other embodiments, R ¹² is C ₇ alkyl. In some embodiments, R ¹² is C ₈ alkyl. In yet other embodiments, R ¹² is C ₉ alkyl. In some embodiments, R ¹² is C ₁₀ alkyl. In yet other embodiments, R ¹² is C ₁₁ alkyl. In other embodiments, R ¹² is C ₁₂ alkyl. In still other embodiments, the alkyl moiety is substituted with one or more oxygens to form an ether moiety, for example a methoxymethyl moiety.

In some embodiments, R ¹² is methylamino. In other embodiments, R ¹² is ethylamino. In yet other embodiments, R ¹² is C ₃ aminoalkyl. In some embodiments, R ¹² is C ₄ aminoalkyl. In yet other embodiments, R ¹² is C ₅ aminoalkyl. In some embodiments, R ¹² is C ₆ aminoalkyl. In some embodiments, R ¹² is C ₇ aminoalkyl. In some embodiments, R ¹² is C ₈ aminoalkyl. In yet other embodiments, R ¹² is C ₉ aminoalkyl. In some other embodiments, R ¹² is C ₁₀ aminoalkyl. In yet other embodiments, R ¹² is C ₁₁ aminoalkyl. In other embodiments, R ¹² is C ₁₂ aminoalkyl. In some embodiments, the aminoalkyl is dimethylamino alkyl.

In yet other embodiments, R ¹² is acetyl. In some other embodiments, R ¹² is C ₂ alkylcarbonyl. In some embodiments, R ¹² is C ₃ alkylcarbonyl. In yet other embodiments, R ¹² is C ₄ alkylcarbonyl. In some embodiments, R ¹² is C ₅ alkylcarbonyl. In yet other embodiments, R ¹² is C ₆ alkylcarbonyl. In some other embodiments, R ¹² is C ₇ alkylcarbonyl. In some embodiments, R ¹² is C ₈ alkylcarbonyl. In yet other embodiments, R ¹² is C ₉ alkylcarbonyl. In some other embodiments, R ¹² is C ₁₀ alkylcarbonyl. In some embodiments, R ¹² is C ₁₁ alkylcarbonyl. In other embodiments, R ¹² is C ₁₂ alkylcarbonyl. The alkylcarbonyl is substituted with a carboxy moiety, for example the alkylcarbonyl is substituted to form a succinic acid moiety (ie, 3-carboxyalkylcarbonyl). In another embodiment, the alkyl carbonyl is terminally -SH replaced by a group

In some embodiments, R ¹² is amidyl. In some embodiments, the amidyl comprises an alkyl moiety further substituted, for example with -SH, a carbamate, or a combination thereof. In another embodiment, the amidyl is substituted with an aryl moiety, such as phenyl. In certain embodiments, R ¹² can have Formula (IX):

wherein R ¹⁶ at each occurrence is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, —CN, aryl, or heteroaryl.

In some embodiments, R ¹² is methoxy. In other embodiments, R ¹² is ethoxy. In yet other embodiments, R ¹² is C ₃ alkoxy. In some embodiments, R ¹² is C ₄ alkoxy. In some embodiments, R ¹² is C ₅ alkoxy. In some other embodiments, R ¹² is C ₆ alkoxy. In other embodiments, R ¹² is C ₇ alkoxy. In some other embodiments, R ¹² is C ₈ alkoxy. In some embodiments, R ¹² is C ₉ alkoxy. In other embodiments, R ¹² is C ₁₀ alkoxy. In some embodiments, R ¹² is C ₁₁ alkoxy. In yet other embodiments, R ¹² is C ₁₂ alkoxy.

In certain embodiments, R ¹² is pyrrolidinyl, eg, pyrrolidin-1-yl. In other embodiments, R ¹² is piperidinyl, eg piperidin-1-yl or piperidin-4-yl. In other embodiments, R ¹² is morpholino, eg, morpholin-4-yl. In other embodiments, R ¹² is phenyl, and in further embodiments, said phenyl is substituted, for example with a nitro group. In yet other embodiments, R ¹² is pyrimidinyl, eg pyrimidin-2-yl.

In other embodiments, R ¹³ , R ¹⁴ and R ¹⁵ at each occurrence are independently C ₁ -C ₁₂ alkyl. In some embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is methyl. In yet other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is ethyl. In other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₃ alkyl. In yet other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is isopropyl. In other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₄ alkyl. In some embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₅ alkyl. In some embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₆ alkyl. In other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₇ alkyl. In yet other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₈ alkyl. In other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₉ alkyl. In some embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₁₀ alkyl. In some embodiments R ¹³ , R ¹⁴ or R ¹⁵ is C ₁₁ alkyl. In yet other embodiments, R ¹³ , R ¹⁴ or R ¹⁵ is C ₁₂ alkyl.

As noted above, in some embodiments, R ¹² is amidyl substituted with an aryl moiety. In this regard, ^{each instance of R 16} may be the same or different. In certain of these embodiments, R ¹⁶ is hydrogen. In other embodiments, R ¹⁶ is —CN. In other embodiments, R ¹⁶ is heteroaryl, eg, tretrazolyl. In certain other embodiments, R ¹⁶ is methoxy. In other embodiments, R ¹⁶ is aryl, wherein said aryl is optionally substituted. Optional substitutions in this context include C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, for example methoxy; trifluoromethoxy; halo, for example chloro; and trifluoromethyl.

In other embodiments, R ¹⁶ is methyl. In yet other embodiments, R ¹⁶ is ethyl. In some embodiments, R ¹⁶ is C ₃ alkyl. In some other embodiments, R ¹⁶ is isopropyl. In yet other embodiments, R ¹⁶ is C ₄ alkyl. In other embodiments, R ¹⁶ is C ₅ alkyl. In some embodiments, R ¹⁶ is C ₆ alkyl. In some embodiments, R ¹⁶ is C ₇ alkyl. In some embodiments, R ¹⁶ is C ₈ alkyl. In yet other embodiments, R ¹⁶ is C ₉ alkyl. In some embodiments, R ¹⁶ is C ₁₀ alkyl. In other embodiments, R ¹⁶ is C ₁₁ alkyl. In some embodiments, R ¹⁶ is C ₁₂ alkyl.

In some embodiments, R ¹⁶ is methoxy. In some embodiments, R ¹⁶ is ethoxy. In yet other embodiments, R ¹⁶ is C ₃ alkoxy. In some embodiments, R ¹⁶ is C ₄ alkoxy. In other embodiments, R ¹⁶ is C ₅ alkoxy. In some other embodiments, R ¹⁶ is C ₆ alkoxy. In yet other embodiments, R ¹⁶ is C ₇ alkoxy. In some embodiments, R ¹⁶ is C ₈ alkoxy. In yet other embodiments, R ¹⁶ is C ₉ alkoxy. In some other embodiments, R ¹⁶ is C ₁₀ alkoxy. In some embodiments, R ¹⁶ is C ₁₁ alkoxy. In some other embodiments, R ¹⁶ is C ₁₂ alkoxy.

In some other embodiments, R ⁸ and R ⁹ combine to form a 12-18 membered crown ether. For example, in some embodiments, the crown ether is 18 membered, and in other embodiments the crown ether is 15 membered. In certain embodiments R ⁸ and R ⁹ are joined to form a heterocycle having one of the following formulas (X) or (XI):

또는

or

In some embodiments, R ⁸ , R ⁹ or R ³ is taken ^{together with R 10} to form a 5-7 membered heterocycle. For example, in some embodiments, R ³ is taken ^{together with R 10} to form a 5-7 membered heterocycle. In some embodiments, the heterocycle is 5-membered. In other embodiments, the heterocycle is 7-membered. In some embodiments, the heterocycle is represented by Formula (XII):

In the above formula, Z' represents a 5-7 membered heterocycle. In certain embodiments of formula (XI), R ¹² at each occurrence is hydrogen. For example, bond (B) may have one of the following formulas (B1), (B2) or (B3):

또는

or

In certain other embodiments, R ¹² is C ₁ -C ₁₂ alkylcarbonyl or amidyl, which is further substituted with an arylphosphoryl moiety, eg, a triphenyl phosphoryl moiety. Examples of bonds having such structures include B56 and B55.

In certain embodiments, bond (B) does not have any of the structures A1-A5. Table 2 shows representative binding of types (A) and (B).

Table 2. Representative intersubunit bonds

In subsequent sequences and reviews, this designation for binding is often used. For example, a base comprising a ^{PMO apn bond is exemplified as apn} B, where B is the base. Other bonds are similarly indicated. In addition, an abbreviation may be used, for example, the abbreviation in parentheses may be used (eg, ^a B indicates ^apn B). Other readily identifiable abbreviations may also be used.

B. Oligomers with modified end groups

In addition to carrier peptides, conjugates may also include oligomers comprising modified end groups. Applicants have discovered that modifications at the 3' and/or 5' terminus of oligomers with various chemical moieties provide beneficial therapeutic properties to the conjugate (eg, increased cell delivery, efficacy and/or distribution in tissues, etc.) . In various embodiments, the modified end group comprises a hydrophobic moiety, while in other embodiments the modified end group comprises a hydrophilic group. Modified end groups may be present with or without the bonds described above. For example, in some embodiments, the oligomer to which the carrier peptide is conjugated comprises one or more modified end groups and type (A) linkages, eg, linkages wherein X is —N(CH ₃ ) ₂ . In other embodiments, the oligomer comprises one or more modified end groups and type (B) linkages, eg, linkages wherein X is 4-aminopiperidin-1-yl (ie, APN). In yet another embodiment, the oligomer comprises one or more modified end groups and a mixture of linkages (A) and (B). For example, the oligomer may contain one or more modified end groups (eg, trityl or triphenyl acetyl) and a _{bond wherein X is —N(CH 3} ) _{2 and} a bond wherein X is 4-aminopiperidin-1-yl may include Other combinations of modified end groups and modified linkages also provide beneficial therapeutic properties to the oligomer.

In one embodiment, said oligomer comprising terminal modifications has the formula (XVII): or a salt or isomer thereof:

In the above formula,

X, W and Y are as defined above for any of the bonds (A) and (B);

R ¹⁷ at each occurrence is independently absent, hydrogen or C ₁ -C ₆ alkyl;

R ¹⁸ and R ¹⁹ at each occurrence are independently absent or hydrogen, a carrier peptide, a natural or unnatural amino acid, C ₂ -C ₃₀ alkylcarbonyl, —C(=O)OR ²¹ or R ²⁰ ;

R ²⁰ at each occurrence is independently guanidinyl, heterocyclyl, C ₁ -C ₃₀ alkyl, C ₃ -C ₈ cycloalkyl; C ₆ -C ₃₀ aryl, C ₇ -C ₃₀ aralkyl, C ₃ -C ₃₀ alkylcarbonyl, C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ cycloalkylalkylcarbonyl, C ₇ -C ₃₀ Arylcarbonyl, C ₇ -C ₃₀ Aralkylcarbonyl, C ₂ -C ₃₀ Alkyloxycarbonyl, C ₃ -C ₈ Cycloalkyloxycarbonyl, C ₇ -C ₃₀ Aryloxycarbonyl, C ₈ -C ₃₀ aralkyloxycarbonyl, or —P(=O)(R ²² ) ₂ ;

Pi is, at each occurrence, independently a base pair moiety;

L ¹ is selected from alkyl, hydroxyl, alkoxy, alkylamino, amide, ester, disulfide, carbonyl, carbamate, phosphorodiamidate, phosphoroamidate, phosphorothioate, piperazine and phosphodiester an optional linker of up to 18 atoms in length, including bonds; Also

x is an integer of 0 or more; Also wherein at least one of ^{R 18} or R ^{19 is R 20} ; Also

wherein at least one of ^{R 18} or R ^{19 is R 20} , with the proviso ^{that neither R 17} nor R ¹⁸ is present.

Oligomers with modified end groups may comprise any number of linkages of types (A) and (B). For example, the oligomer may comprise only linkage type (A). For example, X in each bond may be _{—N(CH 3} ) _{2 .} Alternatively, the oligomer may only comprise linkages (B). In certain embodiments, the oligomer comprises a mixture of linkages (A) and (B), for example between 1 and 4 type (B) linkages and the remaining linkages are of type (A). Linkages in this context include, but are not limited to, linkages wherein X is aminopiperidinyl for type (B) and dimethylamino for type (A).

In some embodiments, R ¹⁷ is absent. In some embodiments, R ¹⁷ is hydrogen. In some embodiments, R ¹⁷ is C ₁ -C ₆ alkyl. In some embodiments, R ¹⁷ is methyl. In yet other embodiments, R ¹⁷ is ethyl. In some embodiments, R ¹⁷ is C ₃ alkyl. In some embodiments, R ¹⁷ is isopropyl. In other embodiments, R ¹⁷ is C ₄ alkyl. In yet other embodiments, R ¹⁷ is C ₅ alkyl. In some other embodiments, R ¹⁷ is C ₆ alkyl.

In other embodiments, R ¹⁸ is absent. In some embodiments, R ¹⁸ is hydrogen. In some embodiments, R ¹⁸ is a carrier peptide. In some embodiments, R ¹⁸ is a natural or unnatural amino acid, eg, trimethylglycine. In some embodiments, R ¹⁸ is R ²⁰ .

In other embodiments, R ¹⁹ is absent. In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ¹⁹ is a carrier peptide. In some embodiments, R ¹⁹ is a natural or unnatural amino acid, eg, trimethylglycine. In some embodiments, R ¹⁹ is —C(=O)OR ¹⁷ , for example R ¹⁹ can have the formula:

In other embodiments, R ¹⁸ or R ¹⁹ is C ₂ -C ₃₀ alkylcarbonyl, eg —C(=O)(CH ₂ ) _n CO ₂ H, wherein n is 1-6, eg 2 to be. In other instances, R ¹⁸ or R ¹⁹ is acetyl.

In some embodiments, R ²⁰ at each occurrence is independently guanidinyl, heterocyclyl, C ₁ -C ₃₀ alkyl, C ₃ -C ₈ cycloalkyl; C ₆ -C ₃₀ aryl, C ₇ -C ₃₀ aralkyl, C ₃ -C ₃₀ alkylcarbonyl, C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ cycloalkylalkylcarbonyl, C ₆ -C ₃₀ Arylcarbonyl, C ₇ -C ₃₀ Aralkylcarbonyl, C ₂ -C ₃₀ Alkyloxycarbonyl, C ₃ -C ₈ Cycloalkyloxycarbonyl, C ₇ -C ₃₀ Aryloxycarbonyl, C ₈ -C ₃₀ aralkyloxycarbonyl, -C(=O)OR ²¹ , or -P(=O)(R ²² ) ₂ , wherein R ²¹ _{is C 1} -C comprising one or more oxygen or hydroxyl moieties or combinations thereof. ₃₀ alkyl, and each R ²² is C ⁶ -C ¹² aryloxy.

in certain other embodiments. R ¹⁹ is —C(=O)OR ²¹ and R ¹⁸ is hydrogen, guanidinyl, heterocyclyl, C ₁ -C ₃₀ alkyl, C ₃ -C ₈ cycloalkyl; C ₆ -C ₃₀ aryl, C ₃ -C ₃₀ alkylcarbonyl, C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ cycloalkylalkylcarbonyl, C ₇ -C ₃₀ arylcarbonyl, C ₇ -C ₃₀ aralkylcarbonyl, C ₂ -C ₃₀ alkyloxycarbonyl, C ₃ -C ₈ cycloalkyloxycarbonyl, C ₇ -C ₃₀ aryloxycarbonyl, C ₈ -C ₃₀ aralkyloxycarbonyl, or - P(=O)(R ²² ) ₂ , wherein each R ²² is C ⁶ -C ¹² aryloxy.

In other embodiments, R ²⁰ at each occurrence is independently guanidinyl, heterocyclyl, C ₁ -C ₃₀ alkyl, C ₃ -C ₈ cycloalkyl; C ₆ -C ₃₀ aryl, C ₃ -C ₃₀ alkylcarbonyl, C ₃ -C ₈ cyclocarbonyl, C ₃ -C ₈ cycloalkylalkylcarbonyl, C ₇ -C ₃₀ arylcarbonyl, C ₇ -C ₃₀ aralkylcarbonyl, C ₂ -C ₃₀ alkyloxycarbonyl, C ₃ -C ₈ cycloalkyloxycarbonyl, C ₇ -C ₃₀ aryloxycarbonyl, C ₈ -C ₃₀ aralkyloxycarbonyl, or -P (=O)(R ²² ) ₂ . In other instances, R ²⁰ at each occurrence is independently guanidinyl, heterocyclyl, C ₁ -C ₃₀ alkyl, C ₃ -C ₈ cycloalkyl; C ₆ -C ₃₀ aryl, C ₇ -C ₃₀ aralkyl, C ₃ -C ₈ cycloalkylcarbonyl, C ₃ -C ₈ cycloalkylalkylcarbonyl, C ₇ -C ₃₀ arylcarbonyl, C ₇ -C ₃₀ aralkylcarbonyl, C ₂ -C ₃₀ alkyloxycarbonyl, C ₃ -C ₈ cycloalkyloxycarbonyl, C ₇ -C ₃₀ aryloxycarbonyl, C ₈ -C ₃₀ aralkyloxycarbonyl, or -P (=O)(R ²² ) ₂ .

In some embodiments, R ²⁰ is guanidinyl, for example mono methylguanidinyl or dimethylguanidinyl. In other embodiments, R ²⁰ is heterocyclyl. For example, in some embodiments, R ²⁰ is piperidin-4-yl. In some embodiments, piperidin-4-yl is substituted with a trityl or Boc group. In other embodiments, R ²⁰ is C ₃ -C ₈ cycloalkyl. In other embodiments, R ²⁰ is C ₆ -C ₃₀ aryl.

In some embodiments, R ²⁰ is C ₇ -C ₃₀ arylcarbonyl. For example, in some embodiments, R ²⁰ has the formula (XVIII):

wherein R ²³ at each occurrence is independently hydrogen, halo, C ₁ -C ₃₀ alkyl, C ₁ -C ₃₀ alkoxy, C ₁ -C ₃₀ alkyloxycarbonyl, C ₇ -C ₃₀ aralkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, wherein one R ²³ is joined with the other R ²³ to form a heterocyclyl ring. In some embodiments, at least one R ²³ is hydrogen, for example in some embodiments each R ²³ is hydrogen. In other embodiments, at least one R ²³ is C ₁ -C ₃₀ alkoxy, eg in some embodiments, each R ²³ is methoxy. In other embodiments, at least one R ²³ is heteroaryl, for example in some embodiments, at least one R ²³ has one of the following formulas (XVIIIa) or (XVIIIb):

또는

or

In still other embodiments, one R ²³ is joined with the other R ²³ to form a heterocyclyl ring. For example in one embodiment, R ²⁰ is 5-carboxyfluorescein.

In other embodiments, R ²⁰ is C ₇ -C ₃₀ aralkylcarbonyl. For example, in various embodiments, R ²⁰ has one of the following formulas (XIX), (XX), or (XXI):

또는

or

wherein R ²³ at each occurrence is independently hydrogen, halo, C ₁ -C ₃₀ alkyl, C ₁ -C ₃₀ alkoxy, C ₁ -C ₃₀ alkyloxycarbonyl, C ₇ -C ₃₀ aralkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, wherein R ²³ is taken with another R ²³ to form a heterocyclyl ring, X is —OH or halo and m is an integer from 0 to 6. In some specific embodiments, m is 0. In other embodiments, m is 1, while in other embodiments m is 2. In other embodiments, at least one R ²³ is hydrogen, for example in some embodiments each R ²³ is hydrogen. In some embodiments, X is hydrogen. In other embodiments, X is —OH. In another embodiment X is Cl. In other embodiments, at least one R ²³ is C ₁ -C ₃₀ alkoxy, eg methoxy.

In still other embodiments, R ²⁰ is C ₇ -C ₃₀ aralkyl, eg trityl. In another embodiment R ²⁰ is methoxy trityl. In some embodiments, R ²⁰ has the formula (XXII):

wherein R ²³ at each occurrence is independently hydrogen, halo, C ₁ -C ₃₀ alkyl, C ₁ -C ₃₀ alkoxy, C ₁ -C ₃₀ alkyloxycarbonyl, C ₇ -C ₃₀ aralkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, and one R ²³ is combined with the other R ²³ to form a heterocyclyl ring. For example, in some embodiments each R ²³ is hydrogen. In other embodiments, at least one R ²³ is C ₁ -C ₃₀ alkoxy, eg methoxy.

In another embodiment, R ²⁰ is C ₇ -C ₃₀ aralkyl and R ²⁰ has the formula (XXIII):

In some embodiments, at least one R ²³ is halo, for example it is chloro In some other embodiments, one R ²³ is chloro in the para position.

In other embodiments, R ²⁰ is C ₁ -C ₃₀ alkyl. For example, in some embodiments, R ²⁰ is C ₄ -C ₂₀ alkyl and optionally includes one or more double bonds. For example, in some embodiments, R ²⁰ is C ₄ containing a triple bond, for example, the terminal triple bond is ₁₀ alkyl. In some embodiments, R ²⁰ is hexyn-6-yl. In some embodiments, R ²⁰ has one of the following formulas (XXIV), (XXV), (XXVI), or (XXVII):

또는

or

In yet other embodiments, R ²⁰ is C ₃ -C ₃₀ alkylcarbonyl, eg C ₃ -C ₁₀ alkyl carbonyl. In some embodiments, R ²⁰ is —C(=O)(CH ₂ ) _p SH or —C(=O)(CH ₂ ) _p SSHet, wherein p is an integer from 1 to 6 and Het is heteroaryl. For example p may be 1 or p may be 2. In another example Het is pyridinyl, for example pyridin-2-yl. In other embodiments, the C ₃ -C ₃₀ alkylcarbonyl is substituted with an additional oligomer, for example in some embodiments the oligomer comprises a C ₃ -C ₃₀ alkyl carbonyl at the 3′ position of the other oligomer. . Such terminal modifications are included within the scope of the present invention.

In other embodiments R ²⁰ _{is C 3} -C ₃₀ alkyl carbonyl further substituted with an arylphosphoryl moiety, for example triphenyl phosphoryl. Examples of such R ²⁰ groups include structure 33 in Table 3.

In another example, R ²⁰ is C ₃ -C ₈ cycloalkylcarbonyl, eg C ₅ -C ₇ alkylcarbonyl. In these embodiments, R ₂₀ has the formula (XXVIII):

wherein R ²³ at each occurrence is independently hydrogen, halo, C ₁ -C ₃₀ alkyl, C ₁ -C ₃₀ alkoxy, C ₁ -C ₃₀ alkyloxycarbonyl, C ₇ -C ₃₀ aralkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, and one R ²³ is combined with the other R ²³ to form a heterocyclic ring. In some embodiments, R ²³ is heterocyclylalkyl, for example in some embodiments R ²³ has the formula:

In some other embodiments, R ²⁰ is C ₃ -C ₈ cycloalkylalkylcarbonyl. In other embodiments, R ²⁰ is C ₂ -C ₃₀ alkyloxycarbonyl. In other embodiments, R ²⁰ is C ₃ -C ₈ cycloalkyloxycarbonyl. In other embodiments, R ²⁰ is C ₇ -C ₃₀ aryloxycarbonyl. In other embodiments, R ²⁰ is C ₈ -C ₃₀ aralkyloxycarbonyl. In other embodiments, R ²⁰ is —P(=O)(R ²² ) ₂ , each R ²² is C ⁶ -C ¹² aryloxy, eg, in some embodiments, R ²⁰ is of the formula (C24 ) has:

In other embodiments, R ²⁰ comprises one or more halo atoms. For example in some embodiments R ²⁰ comprises a perfluoro analog of any one of ^{the R 20 moieties above.} In other embodiments, R ²⁰ is p-trifluoromethylphenyl, trifluoromethyltrityl, perfluoropentyl, or pentafluorophenyl.

In some embodiments, the 3' end comprises a modification, and in other embodiments the 5' end comprises a modification. In other embodiments, both the 3' and 5' ends contain modifications. Thus in some embodiments R ¹⁸ is absent and R ¹⁹ is R ²⁰ . In other embodiments R ¹⁹ is absent and R ¹⁸ is R ²⁰ . In yet other embodiments R ¹⁸ and R ¹⁹ are each R ²⁰ .

In some embodiments, the oligomer comprises a cell penetrating peptide in addition to a 3' or 5' modification. Thus in some embodiments R ¹⁹ is a cell penetrating peptide and R ¹⁸ is R ²⁰ . In other embodiments, R ¹⁸ is a cell penetrating peptide and R ¹⁹ is R ²⁰ . In a further embodiment of the foregoing, the cell penetrating peptide is an arginine rich peptide.

In some embodiments, the linker L ¹ that attaches the 5′ end group (ie R ¹⁹ ) to the oligomer may be present or absent. A linker may comprise any number of functional groups and lengths, provided that the linker retains the ability to bind the 5' end group to the oligomer and the linker does not interfere with the ability of the oligomer to bind the target sequence in a sequence specific manner. . In one embodiment S, L comprises phosphorodiamidate and piperazine linkages. For example, in some embodiments, L has the formula (XXIX):

wherein R ²⁴ is absent, hydrogen or C ₁ -C ₆ alkyl. In some embodiments, R ²⁴ is absent. In some embodiments, R ²⁴ is hydrogen. In some embodiments, R ²⁴ is C ₁ -C ₆ alkyl. In some embodiments, R ²⁴ is methyl. In some embodiments, R ²⁴ is ethyl. In yet other embodiments, R ²⁴ is C ₃ alkyl. In some embodiments, R ²⁴ is isopropyl. In some further embodiments, R ²⁴ is C ₄ alkyl. In some embodiments, R ²⁴ is C ₅ alkyl. In yet other embodiments, R ²⁴ is C ₆ alkyl.

In still other embodiments, R ²⁰ is C ₃ -C ₃₀ alkylcarbonyl and R ²⁰ has the formula (XXX):

wherein R ²⁵ is hydrogen or —SR ²⁶ , wherein R ²⁶ is hydrogen, C ₁ -C ₃₀ alkyl, heterocyclyl, aryl or heteroaryl and q is an integer from 0 to 6.

In a further embodiment of any one of the above, R ²³ at each occurrence is independently hydrogen, halo, C ₁ -C ₃₀ alkyl, C ₁ -C ₃₀ alkoxy, aryl, heteroaryl, heterocyclyl, or heterocyclealkyl. .

In some other embodiments, only the 3' end of the oligomer is conjugated to any one of the groups indicated above. In some other embodiments, only the 5' end of the oligomer is conjugated to any one of the groups indicated above. In other embodiments, both the 3' and 5' ends contain one of the groups indicated above. The terminal group may be selected from any of the groups indicated above or from any of the specific groups exemplified in Table 3.

Table 3. Representative end groups

C. Properties of Conjugates

As noted above, the present invention relates to a conjugate of a carrier peptide and an oligonucleotide analog (ie, an oligomer). An oligomer can contain various modifications that confer various properties (eg, increased antisense activity) to the oligomer. In certain embodiments, the oligomer comprises a backbone comprising a sequence of morpholino ring structures linked by intersubunit bonds, wherein the intersubunit bond comprises one morpholino ring structure at the 5'-terminus of adjacent morpholino ring structures. It connects the 3' ends of the polino ring structure, wherein each morpholino ring structure is bound to a base pair moiety, so that the oligomer can bind to the target nucleic acid in a sequence specific manner. The morpholino ring structure may have the following formula (i):

Wherein Pi is independently at each occurrence a base pair moiety.

Each morpholino ring structure supports a base pairing moiety (Pi) to form a base pairing moiety, which is typically designed to hybridize to a selected antisense target in a cell or in the subject being treated. The base pair moiety can be native DNA or RNA (A, G, C, T, or U) or an analog, such as hypoxanthine (a base compound of the nucleoside indosine) or 5-methyl cytosine. Analog bases that confer improved binding affinity to the oligomer may also be used. Exemplary analogs in this regard include C5-propynyl-modified pyrimidines, 9-(aminoethoxy)phenoxazine (G-clamp), and the like.

As noted above, the oligomer may be modified in accordance with one aspect of the present invention to modify one or more (B) linkages, for example up to about 1, typically 10 uncharged linkages for every 2 to 5 uncharged linkages. Each may contain 3 to 5 uncharged bonds. Certain embodiments also include one or more type (B) bonds. In some embodiments, optimal improvement in antisense activity occurs when up to about half of the backbone bonds are of type (B). Although not the greatest improvement, some typically appear with a small number of (B) bonds, for example 10-20%.

In one embodiment, the bond types (A) and (B) are interspersed along the backbone. In some embodiments, the oligomer does not have strict alternating conformations of (A) and (B) along its entire length. In addition to the carrier peptide, the oligomer may optionally contain 5' and/or 3' modifications as described above.

Also contemplated are oligomers having (A) blocks of linkages and (B) blocks of linkages, e.g., (A) the central block of linkages may be flanked by blocks of linkages (B) or vice versa. have. In one embodiment, the oligomers are approximately the same length 5', 3; Also, the percentage of (B) or (A) in the central region is at least about 50%, at least about 70%. Oligomers used for antisense applications generally range from about 10 to about 40 subunits in length, more preferably from about 15 to 25 subunits in length. For example, an oligomer of the invention having 19 to 20 subunits, which is a useful length for antisense oligomers, would ideally contain 2 to 7, such as 4 to 6, or 3 to 5 (B) linkages and the remainder (A) ) can have a bond. An oligomer having 14 to 15 subunits may ideally have 2 to 5, eg 3 or 4 (B) linkages and the remainder (A) linkages.

Morpholino subunits may also be linked by non-phosphorus-basic intersubunit bonds as further described below.

Other oligonucleotide analog linkages that are uncharged in their unmodified state but may have branched amine substituents may also be used. For example, a 5' nitrogen atom on a morpholino ring can be used in a sulfamide bond (or a urea bond when phosphorus is replaced by carbon or sulfur, respectively).

In some embodiments, for antisense applications, the oligomer may be 100% complementary to the nucleic acid target sequence, or the oligomer and the nucleic acid target sequence are used to maintain the action of cellular cellulase and other types of degradation that may occur in vitro. Mismatches may be included, for example, to accommodate variants as long as they are sufficiently stable. Mismatches, if present, are more unstable towards the terminal region of the hybrid duplex than in the center. The number of mismatches allowed will depend on the length of the CleQ oligomer, the percentage of G:C base pairs in the duplex, and the position of the mismatch(s) in the duplex, in accordance with the well-understood principles of duplex stability. Although these antisense oligomers are not necessarily 100% complementary to the nucleic acid target sequence, they are effective in stably and specifically binding to the target sequence so that the biological activity of the nucleic acid target, for example, the expression of the encoding protein(s) is modulated. .

The stability of the duplex formed between the oligomer and the target sequence is the sensitivity of the duplex to perfusion of _{binding T m and cellular enzymatic cleavage. The T m} of the antisense compound for the complementary sequence RNA is determined by conventional methods, for example, Hames et al. , Nucleic Acid Hybridization, IRL Press, 1985, pp.107-108 or Miyada CG and Wallace RB, 1987, Oligonucleotide hybridization techniques, Methods Enzymol. Vol. 154 pp. 94-107.

_{In some embodiments, each antisense oligomer has a binding T m} to complementary sequence RNA above body temperature or in other embodiments 50° C. or higher. In other embodiments, T _m is in the range of 60-80°C or higher. According to a well-known principle, the T _m of an oligomer for a complementary base RNA hybrid can be increased by increasing the ratio of C:G pair bases in the duplex and/or by increasing the length (in base pairs) of the heteroduplex. At the same time, for the purpose of optimizing cell uptake, it may be advantageous to limit the size of the oligomers. For this reason, compounds that exhibit high Tm (50° C. or higher) at lengths of 20 bases or less are generally preferred over those requiring high Tm values of 20 or more bases. For some applications, longer oligomers, for example longer than 20 bases, may have certain advantages. For example, in certain embodiments longer oligomers may find particular utility for use in exon skipin or splice regulation.

The target sequence base may be a normal DNA base or an analog thereof, for example, uracil and inosine capable of Watson-Crick base pairing to a target-sequence RNA base.

Oligomers may also incorporate guanine bases in place of adenine when the target nucleotide is a uracin residue. This is useful when the target sequence varies across different viral species and also the change at any given nucleotide residue is cytosine or uracil. By using guanyl in the targeting oligomer at a point of variability, the well-known ability of guanine to base pair with uracil (termed C/U:G base pairing) can be exploited. By incorporating guanines at these positions, a single oligomer can effectively target a wide range of RNA target variability.

The compounds (eg, oligomers, intersubunit bonds, end groups) may exist in different isomeric forms, such as structural isomers (eg, tautomers). With respect to stereoisomers, the compounds may possess chiral centers and may also occur as racemates, enantiomerically enriched mixtures, individual enantiomers, mixtures or diastereomers or individual diastereomers. All such isomeric forms are included within the scope of the present invention, including mixtures thereof. The compounds may also have axial chirality that can give rise to atropisomers. Moreover, some of the crystalline forms of the compounds may exist as polymorphs within the scope of the present invention. In addition, some of the compounds may form solvates with water or other organic solvents. Such solvates are likewise included within the scope of the present invention.

The oligomers described herein can be used in methods of inhibiting the production of proteins or replication of viruses. Thus in one embodiment the nucleic acid encoding such a protein is exposed to an oligomer as described herein. In a further embodiment of the foregoing, the antisense oligomer comprises a 5' or 3' modified end group or a combination thereof as described herein, and the base portion B of the nucleic acid at a position effective to inhibit the production of the protein. Some form a sequence effective to hybridize. In one embodiment, the position is the ATG start codon region of an mRNA, a spliced portion of a pre-mRNA, or a viral target sequence as described herein.

_{In one embodiment, the oligomer has a T m} for binding to a target sequence of at least about 50° C. and is also taken up by mammalian or bacterial cells. In another embodiment, the oligomer can be conjugated to a transport moiety, such as an arginine rich peptide as described herein, to facilitate such uptake. In another embodiment, the terminal modifications described herein can act as a transport moiety to facilitate uptake by mammalian and/or bacterial cells.

The preparation and properties of morpholino oligomers are described in greater detail below and are also described in US Pat. No. 5,185,444 and International Publication No. WO/2009/064471, each of which is incorporated herein by reference in its entirety.

D. Formulation and Administration of Conjugates

The present invention also provides for the formulation and delivery of the disclosed conjugates. Thus in one embodiment the invention relates to a composition comprising a peptide-oligomer conjugate as described herein and a pharmaceutically acceptable excipient.

Effective delivery of a conjugate to a target nucleic acid is an important aspect of therapy. Routes of antisense oligomer delivery include, but are not limited to, oral and parenteral routes including, but not limited to, inhalation, transdermal, and topical delivery, as well as a variety of systemic routes including intravenous, subcutaneous, intraperitoneal, and intramuscular. Appropriate routes can be determined by one of ordinary skill in the art as appropriate to the symptoms of the subject being treated. For example, the appropriate route of delivery of antisense oligomers in the treatment of viral infections of the skin is topical delivery, whereas delivery of antisense oligomers for the treatment of viral respiratory infections is inhalation. Oligomers can also be delivered directly to the site of viral infection or into the bloodstream.

The conjugates may be administered in any convenient excipient that is physiologically and/or pharmaceutically acceptable. Such compositions may include various pharmaceutically acceptable carriers used by those of ordinary skill in the art. Examples thereof include, but are not limited to, saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions such as oil/water emulsions or triglyceride emulsions, tablets and capsules. The selection of an appropriate physiologically acceptable carrier will depend upon the mode of administration chosen.

The compounds (eg, conjugates) of the present invention can generally be used as free acids or free bases. Alternatively, the compounds of the present invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art and may also be formed from organic and inorganic acids. Suitable organic acids are malic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid. Base addition salts include those salts that form with carboxylate anions, as well as organic and inorganic cations such as those selected from alkali and alkaline earth metals (eg lithium, sodium, potassium, manganese, barium and calcium). salts formed with organic and inorganic cations such as those selected from ammonium ions and substituted derivatives thereof (eg dibenzyl ammonium, benzyl ammonium, 2-hydroxyethylammonium, etc.). Accordingly, the term "pharmaceutically acceptable salt" of formula (I) is intended to include any and all acceptable salt forms.

In addition, prodrugs are also included within the context of the present invention. A prodrug is any covalent carrier that releases a compound of formula (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in such a way that the modifications are cleaved either by routine manipulation or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group that, when administered, cleaves to form a hydroxy, amine or sulfhydryl group. Accordingly, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups of compounds of formula (I). Additionally, in the case of carboxylic acid (-COOH), esters such as methyl esters, ethyl esters and the like can be used.

In some cases, liposomes can be used to promote the uptating of antisense oligonucleotides into cells (eg, Williams, SA, Leukemia 10(12):1980-1989, 1996; Lappalainen et al., Antiviral Res. 23 :119, 1994; Uhlmann et al., Antisense Oligonucleotides: A New Therapeutic Principle, Chemical Reviews, Volume 90, No. 4, pages 544-584, 1990; Gregoriadis, G., Chapter 14, Liposomes, Drug Carriers in Biology and Medicine, pp. 287-341, Academic Press, 1979). Hydrogels can also be used as excipients for the administration of antisense oligomers, for example as described in WO 93/01286. Alternatively, the oligonucleotides may be administered as microspheres or microparticles. (See, eg, Wu, G.Y. and Wu, C.H., J. Biol. Chem. 262:4429-4432, 1987). Alternatively, the use of gas-filled microbubbles complexed with antisense oligomers may increase delivery to target tissues as described in US Pat. No. 6,245,747. Sustained release compositions may also be used. They may include semipermeable polymer matrices in the form of films or molded articles such as microcapsules.

In one embodiment, antisense inhibition is an antisense agent effective to inhibit the replication of a specific virus, effective to treat infection of a host animal by or by contacting an infected cell with the virus. The antisense agent is administered to a mammalian subject, such as a human or livestock, infected with a given virus in an appropriate pharmaceutical carrier. Antisense oligonucleotides are considered to inhibit the growth of RNA viruses in the host. RNA viruses can be reduced in number or eliminated effects that are somewhat detrimental to the normal growth or development of the host.

In one aspect of the method, the subject is a human subject, eg, a patient diagnosed as having a local or systemic viral infection. The patient's symptoms may also include, for example: (1) reduced immunity; (2) is a burn victim; (3) having an indwelling catheter; or (4) in the case of a patient who is about to undergo surgery or who has recently undergone surgery, the prophylactic administration of the antisense oligomer of the present invention may be affected. In one preferred embodiment, the oligomer is a phosphorodiamidate morpholino oligomer contained in a pharmaceutically acceptable carrier and is also delivered orally. In another preferred embodiment, the oligomer is a phosphorodiamidate morpholino oligomer contained in a pharmaceutically acceptable oligomer and is also delivered intravenously (i.v.).

In another application of the method, the subject is a livestock animal such as chicken, turkey, pig, cow or goat, and the treatment is prophylactic or therapeutic. The present invention also encompasses livestock and poultry edible compositions containing edible grains supplemented with sub-therapeutic amounts of antiviral antisense compounds of the type described above. Improvements are also contemplated for methods of supplying livestock and poultry with edible grains supplemented with subtherapeutic levels of antiviral agents, wherein said edible grains are supplemented with subtherapeutic amounts of antiviral oligonucleotides as described above.

In one embodiment, the conjugate is administered in an amount and method effective to result in a peak blood concentration of at least 200-400 nM antisense oligomer. Typically, one or more doses of the antisense oligomer are administered, usually at regular intervals for about 1 to 2 weeks. A preferred dose for oral administration is about 1-1000 mg oligomer per 70 kg. In some cases, doses of 1000 mg or more of oligomer/patient may be required. For intravenous administration, a preferred dosage is about 0.5 mg to 1000 mg of oligomer per 70 kg. The conjugates are administered daily at regular intervals for a short period of time, eg, for two weeks or less. However, in some cases the conjugate is administered intermittently for a longer period of time. Administration may be subsequent to or concurrent with administration of an antibiotic or other therapeutic treatment. The treatment regimen can be adjusted as indicated (dose, frequency, route, etc.) based on immunoassays, other biochemical tests, and physiological tests of the subject being treated.

Effective in vivo treatment regimens using the conjugates of the present invention may vary depending on the duration, dosage, frequency and route of administration, as well as the symptoms of the subject being treated (i.e., prophylaxis versus administration in response to a local or systemic infection). enemy administration). Thus, to achieve optimal therapeutic results, such in vivo therapies will often require monitoring by testing appropriate for the particular type of viral infection being treated and also corresponding adjustments in dosage or treatment regimen. Treatment may be monitored by general signs of disease and/or infection, such as complete blood count (CBC), nucleic acid detection methods, immunodiagnostic tests, viral cultures, or detection of heteroduplexes.

The effect of an in vivo administered antiviral conjugate of the present invention in inhibiting or abrogating the growth of one or more types of RNA virus is a biological sample (tissue, blood, urea, etc.) taken from a subject before, during and after administration of the antisense oligomer. can be determined from Analysis of the sample can be performed by (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences using procedures known to those skilled in the art, for example, electrophoretic gel mobility assays; (2) monitoring viral protein production as measured by standard techniques such as ELISA or Western blotting; or (3) determining the effect on virus titer, for example by the method of Spearman-Karber. (See, e.g., Pari, GS et al., Antimicrob. Agents and Chemotherapy 39(5):1157-1161, 1995; Anderson, KP et al., Antimicrob. Agents and Chemotherapy 40(9):2004-2011, 1996 , Cottral, GE (ed) in: Manual of Standard Methods for Veterinary Microbiology, pp. 60-93, 1978).

E. Preparation of Conjugates

Morpholino subunits, linkages between modifying subunits, and oligomers comprising them may be prepared as described in the Examples and in US Pat. Nos. 5,185,444 and 7,943,762, which are incorporated herein by reference in their entirety. Morpholino subunits can be prepared according to the following general scheme I.

Scheme 1. Preparation of morpholino subunits

Referring to Scheme 1, B represents a base pair moiety, PG represents a protecting group, and a morpholino subunit can be prepared from the corresponding ribinucleoside (1) as shown. The morpholino subunit (2) may be optionally protected by reaction with a suitable protecting group precursor, for example trityl chloride. The 3' protecting group is generally removed during solid state oligomer synthesis as detailed below. The base-pairing moieties may be appropriately protected during solid phase oligomer synthesis. Suitable protecting groups include benzoyl for adenyl and cytosine and pivaloyloxymethyl for hypoxanthi(I). A pivaloyloxymethyl group may be introduced on the N1 position of the hypoxanthine heterocyclic base. Although unprotected hypoxanthine subunits can be used, the yield of the activation reaction is much better when the base is protected. Other suitable protecting groups are described in pending US patent application Ser. No. 12/271,040, which is incorporated herein by reference in its entirety.

Reaction of 3 with an activated phosphorus compound 4 yields a morpholino subunit with the desired binding moiety (5). Compounds of formula 4 can be prepared using any number of methods known to those skilled in the art. For example, such compounds can be prepared by reaction of the corresponding amine with phosphorus oxychloride. In this regard, the amine starting materials may be prepared using any method known in the art, for example, those described in the Examples and in US Pat. No. 7,943,762. Although the above scheme represents type (B) (eg, X is -NR ⁸ R ⁹ ), a bond of type (A) (eg, X is dimethylamine) can be prepared in a similar manner.

The compound of formula 5 can be used in solid phase automated oligomer synthesis for the preparation of oligomers containing small intermolecular bonds. Such methods are well known in the art. Briefly, the compound of formula 5 can be modified at the 5' end to contain a linker on a solid support. For example, compound 5 may be bound to the solid support by a linker comprising L ¹ and/or R ^{19 .} An exemplary method is demonstrated in FIGS. 3 and 4 . In this way, the oligo may contain a 5' end modification after the oligo synthesis is complete and the oligomer is cleaved from the solid support. Once supported, the protecting group of 5 (eg trityl) is removed and the free amine is reacted with the active phosphorus moiety of the second compound of formula 5. This sequence is repeated until an oligomer of the desired length is obtained. The protecting group at the terminal 5' end may be removed or dropped if 5'-modification is desired. The oligo may be removed from the solid support using any number of methods, such as treatment with a base to cleave the bond to the solid support.

Peptide oligomer conjugates are prepared according to standard peptide synthesis methods known in the art with an oligomer comprising free NH (e.g., 3' NH of an amorpholino oligomer) in the presence of an appropriate activator (e.g., HATU) ) can be prepared by coupling. Conjugates can be purified using a number of techniques known in the art, such as SCX chromatography.

The preparation of modified morpholino subunits and peptide oligomer conjugates is described in more detail in the Examples. Peptide oligomeric conjugates comprising any number of modifying linkages can be prepared using the methods described herein, known in the art and/or described herein by reference. Global modifications of PMO+ morpholino oligomers prepared as described above are also described in the Examples (see, eg, PCT Publication No. WO2008036127).

F. Antisense activity of oligomers

The invention also provides a method of inhibiting the production of a protein comprising exposing a nucleic acid encoding the protein to a peptide-oligomeric conjugate as described herein. Thus in one embodiment the nucleic acid encoding such a protein is exposed to a conjugate as described herein, wherein the base pair portion Pi forms a sequence effective to hybridize to a portion of the nucleic acid at a position effective to inhibit production of the protein. do. The oligomer may target, for example, the ATG start codon region of an mRNA, a splice site of a pre-mRNA, or a viral target sequence as described below.

In another embodiment, the invention provides a method of increasing the antisense activity of a peptide oligomer conjugate comprising an oligonucleotide analog having a sequence of intersubunit linkages supporting a base pairing site, the method comprising: and conjugating a carrier peptide as described.

In some embodiments, an increase in antisense activity can be demonstrated by (i) or (ii):

(i) a decrease in the expression of the encoding protein relative to that provided by the corresponding unmodified oligomer if binding of the antisense oligomer to its target sequence is effective to block the translation start codon for the encoding protein, or

(ii) as provided by the corresponding unmodified oligomer if binding of the antisense oligomer to its target sequence, when correctly spliced, is effective to block aberrant splice sites in the pre-mRNA encoding the protein; increased expression of the encoding protein. Assays suitable for the measurement of these effects are further described below. In one embodiment, the modification provides for an increase in such activity in a cell free translation assay, a splice modification translation assay in cell culture, or a splice modification in a functional animal model system as described herein. In one embodiment, the activity is increased by at least 2, at least 5 or at least 10 factors.

Various exemplary applications of the conjugates of the present invention are described below, including antiviral applications, treatment of neuromuscular diseases, bacterial infections, inflammation and polycystic kidney disease. These descriptions are not meant to limit the invention in any way, but rather serve to exemplify the wide range of human and animal disease symptoms that can be addressed using the conjugates described herein.

G. Exemplary Therapeutic Uses of Conjugates

Oligomers conjugated to carrier peptides contain good potency and low toxicity, thus resulting in a better therapeutic window than those obtained using oligomers or peptide-oligomer conjugates. The following description provides illustrative examples of, but not limited to, therapeutic uses of the conjugates.

1. Targeting of stem loop secondary structures of ssRNA viruses

One class of exemplary antisense antiviral compounds comprises a targeting sequence complementary to a sequence of 12-40 subunits and a region associated with a stem loop secondary structure within 40 bases of the 5'-end of the positive-sense RNA strand of the targeted virus. morpholio oligomers as described herein. (See, for example, PCT Publication No. WO/2006/033933 or US Application Publication Nos. 20060269911 and 20050096291, which are incorporated herein by reference in their entirety).

The present invention involves first identifying as a viral target sequence a region within the 5'-terminal 40 bases of the positive strand of an infectious virus whose sequence can form a stem loop secondary structure. Then, by stepwise solid phase synthesis, a morpholino oligomer having a targeting sequence of at least 12 subunits complementary to a region of the viral genome capable of forming an internal double structure is constructed, wherein the oligomer comprises an oligonucleotide compound and a positive sense of the virus. A heteroduplex structure composed of strands and characterized by a dissociation Tm of the stem loop structure at at least 45° C. and disruption of the stem loop structure can be formed together with the viral target sequence. The oligomer is conjugated to a carrier peptide as described herein.

The target sequence is identified by a 5'-end sequence, for example, 40 bases at the 5'-end, by a computer program capable of performing secondary structure prediction based on investigation of the minimum free energy state of the input RNA sequence. can do.

In a related aspect, the conjugate has a single-stranded positive sense genome in a mammalian host cell and also contains Flaviviridae, Picornoviridae, Calicivirus, Togaviridae, Arterivirus. (Arteriviridae), Coronavirus (Coronaviridae), Astrovirus (Astroviridae) or Hepevirus (Hepeviridae) can be used in a method of inhibiting the replication of an RNA virus selected from one of the families. The method described herein has a target sequence of at least 12 subunits complementary to a region within 40 bases of the 5'-end of the 5'-stranded viral genome of the positive-stranded viral genome capable of forming an inner stem ring secondary structure. and administering to the infected host cell a virus inhibiting amount of the conjugate as described. When the conjugate is administered to a host cell, (i) an oligonucleotide compound and a positive sense strand of the virus, and (ii) forms a heteroduplex structure that exhibits disruption of the secondary structure of the stem loop and dissociation at at least 45°C. effective to do The conjugate may be administered to a mammalian subject infected with or at risk of viral infection.

Exemplary targeting sequences targeting the terminal stem loop structures of dengue and Japanese encephalitis viruses are listed below as SEQ ID NOs: 1 and 2, respectively.

Additional exemplary target sequences targeting the terminal stem loop structures of ssRNA viruses can also be found in US Patent Application Serial No. 11/801,885 and PCT Publication No. WO/2008/036127, which are herein incorporated by reference in their entirety.

2. Targeting of the primary open reading frame of ssRNA viruses

A second class of exemplary conjugates are picornaviruses, caliciviruses, togaviruses, coronaviruses, having a first open reading frame encoding a polyprotein containing a plurality of functional proteins and a single-stranded positive sense genome of less than 12 kb; and to inhibit the growth of the flavivirus family. In a specific embodiment, the virus is an RNA virus from the coronavirus family or West Nile, yellow fever, or dengue virus from the flavivirus family. An inhibitory conjugate comprises an antisense oligomer as described herein having a target base sequence that is substantially complementary to a viral target sequence spanning the AUG start site of the first open reading frame of the viral genome. In one embodiment of the method, the conjugate is administered to a mammalian subject infected with a virus. See, for example, PCT Publication No. WO/2005/007805 and US Patent Application Publication No. 2003224353, which are incorporated herein by reference in their entirety.

A preferred target sequence is the region spanning the AUG start of the first open reading frame (ORF1) of the viral genome. The first ORF normally encodes a polyprotein containing nonstructural proteins such as polymerases, helicases and proteases. It is meant that the target sequence "spans the AUG start site" comprises at least 3 bases on one side of the AUG start site and at least two bases on the other side (a total of at least 8 bases). Preferably, it comprises at least 4 bases on each side of the start site (a total of at least 11 bases).

More generally, preferred target sites include targets that are conserved among various viral isolates. Other favorable sites include the IRES (internal ribosome binding site), the transactivation protein binding site, and the initiation site of replication. Complexes and large viral genomes capable of providing multiple overlapping genes can be effectively targeted by targeting the cellular genes that encode for viral invasion and host response to viral presence.

Various viral genome sequences are available from well-known sources such as the NCBI gene bank database. The AUG start site of an ORFI can also be identified in a dependent genetic database or reference, or can be found by scanning the sequence for the AUG codon in the region of the expected ORFI start site.

A general genomic organization for each of the four viral families is provided below, followed by exemplary target sequences obtained for a selected member (genus, species or strain) within each family.

3. Targeting of influenza virus

A third class of exemplary conjugates is used to treat viral infections or inhibit viral growth of the Orthomyxoviridae family. In one embodiment, the host cell is contacted with a conjugate as described herein, eg, a conjugate comprising a sequence effective to hybridize to a target moiety selected from: 1) a negative sense viral RNA segment 5' or 3' terminal 25 bases; 2) the terminal 25 bases of the 5' or 3' end of the positive sense cRNA; 3) 45 bases surrounding the AUG start codon of influenza virus mRNA and; 4) 50 bases surrounding the splice donor or acceptor site of influenza mRNA in alternating splicing. (See, for example, PCT Publication No. WO/2006/047683; US Application Publication No. 20070004661; and PCT Application No. 2010/056613 and US Application No. 12/945,081, which are incorporated herein by reference in their entirety).

Exemplary conjugates in this regard include conjugates comprising an oligomer comprising SEQ ID NO:3.

Table 4. Influenza target sequences introducing modified intersubunit bonds or end groups

**3'-benzhydryl; *+ bond is trimethyl glycine acylated in PMOplus, PMOm represents a T base with a methyl group on the 3-nitrogen position.

The conjugates are particularly useful for treating influenza virus infection in mammals. The conjugate may be administered to a mammalian subject infected with or at risk of influenza virus infection.

4. Viral targeting of the picornavirus family

A fourth class of exemplary conjugates is used to inhibit viral growth of the picornavirus family and also to treat viral infections. The conjugates are particularly useful for treating Enteroviruses and/or Rhinoviruses in mammals. In this embodiment, the conjugate comprises a sequence of 12-40 subunits, comprising at least 12 subunits having a targeting sequence complementary to a region associated with an RNA virus within one of the 32 conserved nucleotide regions of the virus 5' untranslated region. morpholino oligomers having (See, eg, PCT publications WO/2007/030576 and WO/2007/030691 or co-pending co-applicants' US applications 11/518,058 and 11/517,757, which are incorporated herein by reference in their entirety). Exemplary targeting sequences are listed below as SEQ ID NO:6.

5. Virus Targeting of the Flavivirus Family

A fifth class of exemplary conjugates is used to inhibit replication of flaviviruses in animal cells. Exemplary conjugates of this class include at least a region of the positive strand RNA genome of a virus comprising at least a portion of the 3′-CS sequence or 5′-cyclization sequence (5′-CS) of the positive strand flavivirus RNA. and propolino oligomers of 8-40 nucleotides in length with a sequence of 8 bases. A highly preferred target is 3'-CS and also an exemplary target sequence of Dengue Barriers is listed below as SEQ ID NO:7 (eg, PCT International Publication No. WO/2005/030800, incorporated herein by reference in its entirety) or (see pending co-applicant's U.S. Application Serial No. 10/913,996).

6. Virus targeting of the nidovirus family

A sixth class of exemplary conjugates is used to inhibit replication of virus-infected animal cells. Exemplary conjugates of this class are sequences that contain 8 to 25 nucleotide bases and are capable of disrupting base pairs between transcriptional regulatory sequences (TRS) in the 5' leader region of the positive-stranded viral genome and the negative-stranded 3' subgenomic region. (See, for example, PCT International Publication No. WO/2005/065268 or US 20070037763, which is incorporated herein by reference in its entirety).

7. Filovirus Targeting

In another embodiment, the one or more conjugates as described herein are conjugates as described herein, e.g., at least 12 contiguous within the AUG start region of the positive strand mRNA, as further described below. It can be used in a method of inhibiting replication in a host cell by contacting a host cell of Ebola virus or Marburg virus with a conjugate having a target nucleotide sequence complementary to a target sequence composed of nucleotides.

The filovirus genome is approximately 19,000 bases of unsegmented single-stranded RNA in the antisense sequence. The genome encodes seven proteins from a single cistronic mRNA complementary to the vRNA.

The target sequence is a positive strand (sense) RNA sequence that spans or is downstream (within 25 bases) or upstream (within 100 bases) or upstream (within 25 bases) of the 3' terminal 30 bases of the negative strand viral RNA or the AUG start codon of the selected Ebola virus protein. A preferred protein target is L. The nucleoproteins NP and VP30 are also considered viral polymerase subunits VP35 and VP24. Among these, the early protein is preferred, for example VP35 is more preferred than the late expressed L polymerase.

In another embodiment, one or more conjugates as described herein have a target base sequence complementary to the target sequence consisting of at least 12 contiguous bases within the AUG start site region of the positive strand mRNA of the filovirus mRNA sequence. It can be used in a method of inhibiting replication in a host cell by contacting a host cell of Ebola virus or Marburg virus with the conjugate described in (e.g., PCT Publication No. WO/2006/050414 incorporated herein by reference). or U.S. Patent Nos. 7,524,829 and 7,507,196, and U.S. Application Nos. 12/402,455; 12/402,461; 12/402,464; and 12/853,180 and continuation applications).

8. Targeting of Arena Virus

In another embodiment, a conjugate as described herein may be used in a method of inhibiting viral infection of a mammalian cell by a species in the arenavirus family. In one aspect, the conjugate can be used to treat a mammalian subject infected with the virus (see, eg, PCT Publication No. WO/2007/103529 or U.S. Patent No. 7,582,615, herein incorporated by reference). .

Table 5 is an exemplary list of target viruses targeted by the conjugates of the present invention as organized by Old World or New World Arenavirus classification.

Table 5. Targeted arenaviruses

The arenaviral genome consists of two single-stranded RNA segments designated S (small) and L (large). In virions, the molar ratio of S- to L-segment RNA is approximately 2:1. The complete S-segment RNA sequence has been determined for several arenaviruses and ranges from 3,366 to 3,535 nucleotides. The complete L-segment RNA sequence has also been determined for several arenaviruses and ranges from 7,102 to 7,279 nucleotides. The 3' end sequences of the S and L segments are identical at 17 of the last 19 nucleotides. These terminal sequences are conserved among all known arenaviruses. The 5' end 19 or 20 nucleotides at the start of each genomic RNA are imperfectly complementary to the respective 3' end. Because of this complementarity, the 3' and 5' ends are considered base pairs and also form a panhandle structure.

Replication of infectious virions or viral RNA (vRNA) occurs in infected cells to form antigenome, virus-complementary RNA (vcRNA) strands. Both vRNA and vcRNA encode complementary mRNAs. Therefore, arenaviruses are classified as negative- or positive-sense RNA viruses rather than negative- or positive-sense RNA viruses. The yin-positive coexistence arrangement of the viral genes is in both the L- and S-segments. The NP and polymerase genes are located 3' of the S and L vRNA segments, respectively, and also encode in the normal negative sense (ie, they are expressed via transcription of vRNA or genomic complementary mRNA). The genes located at the 5' end of the S and L vRNA segments, ie, GPC and Z, are expressed in mRNA sense, respectively, but there is no evidence that they are translated directly from the genomic vRNA. Instead, these genes are expressed via transcription of genome-sense mRNA from the antigenome (ie vcRNA), and the full-length complementary copy of the genomic vRNA acts as a replicative intermediate.

An exemplary target sequence for the Arenavirus family of viruses is listed as SEQ ID NO:8.

9. Targeting of respiratory syncytial virus

Respiratory syncytial virus (RSV) is one of the most important pathogens in young children. RSV-caused lower respiratory tract symptoms such as bronchiolitis and pneumonia often require hospitalization in children less than one year old. Children with cardiopulmonary disease and children born prematurely are particularly susceptible to severe illness from these infections. RSV infection is also an important disease in older, high-risk adults, and is the second most commonly identified cause of viral pneumonia in the elderly (Falsey, Hennessey et al. 2005). The World Health Organization estimates that RSV is responsible for 64 million clinical infections and 160,000 deaths worldwide each year. There are currently no vaccines available for the prevention of RSV infection. Although many major advances in our understanding of RSV biology, epidemiology, pathophysiology and host immune response have occurred over the past few decades, there continues to be considerable debate regarding the optimal management of infants and children with RSV infection. Lavaririn is the only licensed antiviral agent for the treatment of RSV infection, but its use is limited to high-risk or severely ill infants. The usefulness of ribavirin is limited by its cost, variable efficacy, and propensity to develop resistant viruses (Marquardt 1995; Prince 2001). The current need for additionally effective anti-RSV agents is well recognized.

It is well known that peptide conjugated PMO (PPMO) can be effective in inhibiting RSV both in tissue culture and in animal model systems in vivo (Lai, Stein et al. 2008). Two antisense PPMOs designed to target sequences comprising the 5'-terminal region and the translational start region of RSV L mRNA were tested for anti-RSV activity in culture of two human airway cell lines. One of these, (RSV-AUG-2; SEQ ID NO: 10) reduced _{virus titers by >2.0 log 10.} Intranasal (in) treatment of BALB/c mice with RSV-AUG-2 PPMO before RSV inoculation resulted in _{a decrease in viral titer of 1.2 log 10} in lung tissue 5 days after infection (pi) and attenuated lung infection 7 days after infection. gave rise to These data showed that RSV-AUG-2 gave rise to potent anti-RSV activity that deserves further investigation as a candidate for potential therapeutic applications (Lai, Stein et al. 2008). Despite the success with RSV-AUG-2 PPMO as described above, it is preferred to use the conjugates described herein to account for the toxicity associated with previous peptide conjugates. Thus, in another embodiment of the invention, one or more conjugates as described herein are at least 12 in the AUG start region of anmRNA from a conjugate described herein, for example RSV as detailed below. It can be used in a method of inhibiting replication in a host cell by contacting a RSV host cell with a conjugate having a target nucleotide sequence complementary to a target sequence composed of two adjacent nucleotides.

The L gene of RSV encodes an important component of the viral RNA-dependent RNA polymerase complex. The antisense PPMO designed for the sequence spanning the AUG translation start codon of the RSV L gene mRNA in the form of RSV-AUG-2 PPMO is 13 nt from the "gene start" sequence (GS) located at the 5' end of the L mRNAt within the coding sequence. is complementary to the sequence. Therefore, a preferred L gene target sequence is 22 bases in the L gene coding sequence or any 12 contiguous bases from the 5' end of the L gene mRNA extending 40 bases in the 3' direction as shown in SEQ ID NO: 9 in Table 6 is complementary to Exemplary RSV L gene target sequences are listed below in Table 6 as SEQ ID NOs: 10-14. Any of the inter-subunit modifications described herein can be incorporated into oligomers to provide tissue specificity for antisense activity, increased intracellular delivery, and/or improved therapeutic activity. Exemplary oligomon sequences comprising intersubunit linkages of the present invention are listed in Table 6 below.

Table 6. RSV targets and target sequences

10. Neuromuscular Disorders

In another embodiment, a therapeutic conjugate is provided for use in treating a disease condition associated with a neuromuscular disease in a mammalian subject. The antisense oligomer (eg, SEQ ID NO: 16) was shown to have activity in the MDX mouse model of Duchene muscular dystrophy (DMD). Exemplary oligomeric sequences that introduce linkages used in some embodiments are listed in Table 7. In some embodiments the conjugate comprises an oligomer selected from (a) and (b):

(a) an antisense targeted to human myostatin having a nucleotide sequence complementary to at least 12 adjacent bases in the target region of human myostatin mRNA identified as SEQ ID NO: 18 for treating muscle weakness symptoms as described above oligomers (see, eg, US Patent Application Serial No. 12/493,140, and PCT Publication No. WO2006/086667, incorporated herein by reference). Exemplary murine target sequences are listed as SEQ ID NOs: 19-20; and

(b) antisense capable of producing exon skipping in a DMD protein (dystrophin), such as PMO having a sequence selected from SEQ ID NOs: 22 to 35, for the treatment of DMD as described above, to restore partial activity of the dystrophin protein oligomers (see, eg, PCT International Publications WO/2010/048586 and WO/2006/000057 or US Patent Publication No. 09/061960, which are incorporated herein by reference).

Several other neuromuscular disorders can be treated using the modified bond and end groups of the present invention. Exemplary compounds for treating spinal muscular atrophy (SMA) and myotonic dystrophy (DM) are discussed below.

SMA is an autosomal recessive disease caused by chronic loss of alpha-motor neurons in the spine and can affect children and adults. Reduced expression of survival motor neurons (SMNs) is responsible for the disease (Hua, Sahashi et al. 2010). Although the mutation responsible for SMA is found in the SMN1 gene, the binary gene SMN2 may allow for viability by compensating for the loss of SMN1 when expressed from an alternative splice form lacking exon 7 (delta SMN2). Antisense compounds targeted to intone 6, exon 7 and intron 7 were all shown to induce exon 7 inclusion bodies to varying degrees. Antisense compounds targeted to intron 7 are preferred (see, eg, PCT International Publications WO/2010/148249, WO/2010/120820, WO/2007/002390 and US Patent No. 7838657). Exemplary antisense sequences that target SMN2 pre-mRNA and induce improved exon 7 are listed as SEQ ID NOs: 36-38. Selected modifications of these oligomeric sequences using the modifying linkages and end groups described herein are contemplated to have improved properties over those known in the art. Moreover, any oligomer targeted to intron 7 of the SMN2 gene and comprising the features of the present invention has the potential to induce exon 7 inclusion bodies and is also considered to have potential in SMA patients. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited diseases caused by the expression of toxic RNAs that induce neuromuscular degeneration. DM1 and DM2 are associated with long poly CUG and polyCCUG repeats in the 3'-UTR and intron 1 regions of transcriptional dystrophic myotonica protein kinase (DMPK) and zinc finger protein 9 (ZNF9), respectively (e.g., international publication see WO2008/036406). While normal individuals have as many as 30 CTG repeats, DM1 patients have multiple repeats ranging from 50 to thousands. The severity of the disease and the age of onset are related to the number of repeats. Patients with adult onset show milder symptoms and have less than 100 repetitions. Adolescent-onset DM1 patients have as many as 500 repeats, and congenital cases typically have thousands of CTG repeats. Expanded transcription containing CUG repeats forms a secondary structure, is encased in the nucleus in an intranuclear foci, and also sequesters RNA-binding protein (RNA-BP). Several RNA-BPs have been implicated in diseases involving muscle glial phase (MBNL) protein and CUG-binding protein (CUGBP). The MBNL protein corresponds to the Drosophila muscleblind (Mbl) protein required for photoreceptors and muscle differentiation. MBNL and CUGBP have been identified as antagonistic splicing modulators of transcription affected in DM1, such as cardiac troponin T (cTNT), insulin receptor (IR), and muscle-specific chloride ion channel (ClC-1).

Antisense oligonucleotides targeted to extended repeats of the DMPK gene can displace RNA-BP differentiation and reverse myotonic symptoms in an animal model of DM1 (International Publication No. WO2008/036406). Oligomers comprising the features of the present invention are contemplated to provide improved activity and therapeutic potential for DM1 and DM2 patients. Exemplary sequences targeted to the polyCUG and polyCCUG repeats described above are listed below as SEQ ID NOs: 39-55 and are further described in U.S. Application Serial No. 13/101,942, which is incorporated herein by reference in its entirety.

Additional embodiments of the present invention for treating neuromuscular disorders are contemplated and also include oligomers designed to treat other DNA repeat instability genetic disorders. These diseases include Huntington's disease, spinal cerebellar ataxia, X-linked vertebrae and cerebellar muscular atrophy type 10 (SCA10) as described in WO2008/018795.

Table 7. M23D sequence introducing modification subunit bonds and/or 3' and/or 5' end groups (SEQ ID NO:15)

* Dimerization indicates dimerization by a bond connecting the 3' ends of two monomers. For example, the bond can be -COCH ₂ CH ₂ -S-CH(CONH ₂ )CH ₂ -CO-NHCH ₂ CH ₂ CO- or any other suitable bond. EG3 represents a triethylene glycol tail (see, eg, conjugates in Examples 30 and 31).

11. Antibacterial application

The invention includes in another embodiment a conjugate comprising an antibacterial antisense oligomer for use in treating a bacterial infection in a mammalian host. In some embodiments, the oligomer comprises 10-20 bases and also contains acyl carrier protein (acpP), gyrase A subunit (gyrA), ftsZ, ribosomal protein S10 (rpsJ), leuD, mgtC, pirG, pcaA, and a target sequence of at least 10 contiguous bases complementary to a target region of an infectious bacterial mRNA for the cma1 gene, wherein the target region is a translation start codon of the bacterial mRNA, or upstream of the translation start codon (i.e., 5' ) or within 20 bases in the downstream (ie, 3') direction, wherein the oligomer binds to mRNA to form a heteroduplex, thereby inhibiting bacterial replication.

12. Modulation of nuclear hormone receptors

In another embodiment, the present invention provides a composition for modulating the expression of nuclear hormone receptor (NHR) from the nuclear hormone receptor superfamily (NHRSF), primarily by modulating or modifying splicing of pre-mRNA encoding the receptor. and methods. Examples of specific NHRs include the glucocorticoid receptor (GR), progesterone receptor (PR) and androgen receptor (AR). In certain embodiments, the conjugates described herein induce increased expression of a ligand-independent or other selected form of the receptor and decreased expression of an inactive form.

Embodiments of the present invention provide conjugates comprising oligomers, eg, selected from among the other NHR-regions described herein, of NHRs comprising "ragand-binding exons" and/or contiguous introns of NHRSF pre-mRNAs. Conjugates comprising oligomers complementary to exon or intron sequences are included. The term "ligand-binding exon" is present in wild-type mRNA, but is removed from the primary transcript ("pre-mRNA") to create a ligand-independent form of the mRNA. In certain embodiments, complementarity may be based on a sequence within a sequence of a pre-mRNA spanning a splice site, including but not limited to complementarity based on a sequence spanning an exon-intron junction. does not In other embodiments, complementarity may be based solely on the sequence of introns. In other embodiments, complementarity may be based solely on the sequence of exons (see, eg, US application Ser. No. 13/046,356, incorporated herein by reference).

NHR modulators may be useful for treating NHR-associated diseases, including diseases involving the expression products of genes in which gene transcription is stimulated or repressed by NHR. For example, modulators of NHR that inhibit AP-1 and/or NF-κB may, among other things described herein and known in the art, inflammatory and immune diseases and disorders such as osteoarthritis, rheumatoid arthritis, It may be useful in treating multiple sclerosis, asthma, inflammatory bowel disease, transplant rejection and graft-versus-host disease. Compounds that antagonize transactivation may be useful in treating metabolic diseases associated with elevated concentrations of glucocorticoids such as diabetes, osteoporosis and glaucoma, among others. In addition, compounds that antagonize transactivation may be useful in treating metabolic disorders associated with glucorotticoid deficiency, such as Addison's disease and others.

An embodiment of the present invention comprises a carrier protein and an antisense oligomer composed of morpholino subunits linked by a phosphorus-containing intersubunit bond that bonds one subunit morpholino nitrogen to the 5' exocyclic carbon of an adjacent subunit. A method of modulating nuclear NHR activity or expression in a cell comprising contacting the cell with a conjugate, wherein the oligonucleotide contains 10-40 bases of a target sequence of at least 10 contiguous bases complementary to the target sequence In addition, the target sequence is a pre-mRNA transcript of NHR, thereby regulating the activity or expression of NHR. In certain embodiments, the oligomer alters splicing of the pre-mRNA transcript and also increases expression of variants of NHR. In some embodiments, the oligomer induces full or partial exon skipping of one or more exos of the pre-mRNA transcript. In certain embodiments, said one or more exons encode at least a portion of a ligand binding domain of NHR and said variant is a ligand independent form of NHR. In certain embodiments, said one or more exons encode at least a portion of the trans activation domain of NHR and wherein said variant has reduced transcriptional activation. In certain embodiments, said one or more exons encode at least a portion of a DNA-binding domain of NHR. In certain embodiments, said one or more exons encode at least a portion of the N-terminal activation domain of NHR. In certain embodiments, said one or more exons encode at least a portion of the carboxy-terminal domain of NHR. In a specific embodiment, the variant binds to NF-KB, AP-1, or both and also reduces transcription of one or more of their pro-inflammatory target genes.

In certain embodiments, the oligomer stimulates the transactivation of NHR. In another embodiment, the oligomer antagonizes the transactivation transcriptional activity of NHR. In certain embodiments, the oligomer stimulates the trans-inhibitory activity of NHR. In another embodiment, the oligomer antagonizes the trans-inhibitory activity of NHR. In a specific embodiment, the oligomer antagonizes the transactivating transcriptional activity of NHR and also stimulates the transrepressive activity of NHR (see, e.g., U.S. Patent Application No. 61/313,652, incorporated herein by reference);

Example

Unless otherwise indicated, all chemicals were obtained from Sigma-Aldrich-Fluka. Benzoyl adenosine, benzoyl cytidine and phenylacetyl guanosine were obtained from Carbosynth Limited, UK.

Synthesis of PMO, PMO+, PPMO and PMO comprising additional linkage modifications as described herein is known in the art and in pending US Patent Applications Nos. 12/271,036 and 12/271,040 and PCT International Publication Nos. WO /2009/064471, which is incorporated herein by reference in its entirety.

PMO with 3' trityl modification was synthesized substantially as described in PCT Publication No. WO/2009/064471 except that the detritylation step was omitted.

Example 1.

tert -Butyl 4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

To a suspension of tert -butyl 4-aminopyreridine-1-carboxylate (48.7 g, 0.243 mol) and DIPEA (130 mL, 0.749 mol) in DCM (250 mL) with stirring ethyl trifluoroacetate (35.6 mL) , 0.300 mol) was added. After 20 h, the solution was washed with citric acid solution (200 mL x 3, 10 % w/v aq ) and sodium bicarbonate solution (200 mL x 3, concentrated aq.), dried (MgSO ₄ ), silica (24 g) filtered through. The silica was washed with DCM and the combined eluates were partially concentrated (100 mL) and used directly in the next step. APCI/MS calculated C ₁₂ H ₁₉ F ₃ N ₂ O ₃ 296.1, found m / z = 294.9 (M-1).

Example 2

2,2,2-trifluoro-N-(piperidin-4-yl)acetamide hydrochloride

To a stirred DCM solution of the title compound of Example 1 (100 mL) was added dropwise a solution of hydrogen chloride (250 mL, 1.0 mol) in 1,4-dioxane (4 M). Stirring was continued for 6 h, then the suspension was filtered and the solid was washed with diethyl ether (500 mL) to give the title compound (54.2 g, 96% yield) as a white solid. APCI/MS calculated C ₇ H ₁₁ F ₃ N ₂ O 196.1, found m / z = 196.9 (M+1).

Example 3

(4-(2,2,2-trifluoroacetamido)piperidin-1-yl)phosphonic dichloride

To a cooled (ice/water bath) suspension of the compound of Example 2 (54.2 g, 0.233 mol) in DCM (250 mL) was added phosphorus oxychloride (23.9 mL, 0.256 mol) and DIPEA (121.7 mL, 0.699 mol) dropwise and stirred did After 15 min, the bath was removed and the mixture continued to stir to warm to room temperature. After 1 h, the mixture was partially concentrated (100 mL), the suspension was filtered and the solid was washed with diethyl ether to give the title compound (43.8 g, yield 60%) as a white solid. The eluate was partially concentrated (100 mL), the resulting suspension was filtered, and the solid was washed with diethyl ether to give the additional title compound (6.5 g, 9% yield). ESI/MS calculated: 1-(4-nitrophenyl)pyrerazine derivative C ₁₇ H ₂₂ ClF ₃ N ₅ O ₄ P 483.1, found m / z = 482.1 (M-1).

Example 4

((2S,6S)-6-((R)-5-methyl-2,6-dioxo-1,2,3,6-tetrahydropyridin-3-yl)-4-tritylmorpholine-2 -yl)methyl (4- (2,2,2-trifluoroacetamido) piperidin-1-yl) phosphonochloride

To a stirred, cooled (ice/water bath) solution of the title compound of Example 3 (29.2 g, 93.3 mmol) in DCM (100 mL) Mo(Tr)T # (22.6 g, 46.7 mmol), 2,6- A DCM solution (100 mL) of lutidine (21.7 mL, 187 mmol), and 4-(dimethylamino)pyridine (1.14 g, 9.33 mmol) was added dropwise over 10 min. The bath was allowed to warm to room temperature. After 15 h, the solution was washed with citric acid solution (200 mL×3, 10 % w/v aq ), dried (MgSO ₄ ), concentrated and then the crude oil was loaded directly onto the column. Concentrate fractions of chromatography [SiO ₂ column (120 g), hexanes/EtOAc eluent (gradient 1:1 to 0:1), repeat x 3] to the title compound as a white solid (27.2 g, yield 77%). ESI/MS calculated: 1-(4-nitrophenyl) _{peperazine derivative C 46} H ₅₀ F ₃ N ₈ O ₈ P 930.3, found m / z = 929.5 (M-1).

Example 5

((2S,6R)-6-(6-benzamido-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl(4-(2,2,2-trifluoroa Setamido) piperidin-1-yl) phosphonochloridate

The title compound was synthesized in a similar manner to that described in Example 4 to give the title compound (15.4 g, yield 66%) as a white solid. ESI/MS calculated: 1-(4-nitrophenyl)piperazine derivative C ₅₃ H ₅₃ F ₃ N ₁₁ O ₇ P 1043.4, found m / z = 1042.5 (M-1).

Example 6

(R)-methyl (1-phenylethyl) phosphoramidic dichloride

To a cooled (ice/water bath) solution of phosphorus oxychloride (2.83 mL, 30.3 mmol) in DCM (30 mL) with stirring 2,6-lutidine (7.06 mL, 60.6 mmol) and (R)-(+)- A DCM solution of N ,a-dimethylbenzylamine (3.73 g, 27.6 mmol) was added dropwise successively. After 5 min, the bath was removed and the reaction mixture was allowed to warm to room temperature. After 1 h, the reaction solution was washed with citric acid solution (50 mL x 3, 10 % w/v aq ), dried (MgSO ₄ ), _{filtered through SiO 2} and concentrated to the title compound (3.80 g) as a white foam. was provided. ESI/MS calculated 1-(4-nitrophenyl)piperazine derivative C ₁₉ H ₂₅ N ₄ O ₄ P 404.2, found m / z = 403.1 (M-1).

Example 7

(S)-methyl (1-phenylethyl) phosphoramidic dichloride

The title compound was synthesized in a similar manner to that described in Example 6 to give the title compound (3.95 g) as a white foam. ESI/MS calculated 1-(4-nitrophenyl)piperazine derivative C ₁₉ H ₂₅ N ₄ O ₄ P 404.2, found m / z = 403.1 (M-1).

Example 8

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl Methyl((R)-1-phenylethyl)phosphoramidochloridate

The title compound was synthesized in a similar manner to that described in Example 4 to provide the title chlorophosphoroamidate (4.46 g, 28% yield) as a white solid. ESI/MS calculated C ₃₈ H ₄ 0ClN ₄ O ₅ P 698.2, found m / z = 697.3 (M-1).

Example 9

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyridin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl methyl ((S)-1-phenylethyl)phosphoramidochloridate

The title compound was synthesized in a similar manner to that described in Example 4 to provide the title chlorophosphoroamidate (4.65 g, 23% yield) as a white solid. ESI/MS calculated: C ₃₈ H ₄ 0ClN ₄ O ₅ P 698.2, found m / z = 697.3 (M-1).

Example 10

(4-(pyrrolidin-1-yl)piperidin-1-yl)phosphonic dichloride hydrochloride

To a cooled (ice/water bath) solution of phosphorus oxychloride (5.70 mL, 55.6 mmol) in DCM (30 mL) 2,6-lutidine (19.4 mL, 167 mmol) and 4-(1-pyrrolidinyl)- A DCM solution (30 mL) of piperidine (8.58 g, 55.6 mmol) was added and stirred for 1 h. The suspension was filtered and the solid was washed with excess diethyl ether to give the title pyrrolidine (17.7 g, 91% yield) as a white solid. ESI/MS calculated 1-(4-nitrophenyl)piperazine derivative C ₁₉ H ₃₀ N ₅ O ₄ P 423.2, found m / z = 422.2 (M-1).

Example 11

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydroxypyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl) Methyl (4- (pyrrolidin-1-yl) piperidin-1-yl) phosphonochloridate hydrochloride

To a stirred, cooled (ice/water bath) solution of dichlorophosphoramidate 8 (17.7 g, 50.6 mmol) in DCM (100 mL) in DCM solution of Mo(Tr)T # (24.5 g, 50.6 mmol) (100 mL), 2,6-lutidine (17.7 mL, 152 mmol), and 1-methylimidazole (0.401 mL, 5.06 mmol) were added dropwise over 10 min. The bath was allowed to warm to room temperature and the suspension was stirred. After 6 h, the suspension was poured into diethylether (1 L), stirred for 15 min, filtered and the solid was washed with more ethanol to give a white solid (45.4 g). The crude product was purified by chromatography [SiO ₂ column (120 gram), DCM/MeOH eluent (gradient 1:0 to 6:4)] and the combined fractions were poured into diethyl ether (2.5 L) and stirred for 15 minutes. and the obtained solid was washed with additional ether to give the title compound (23.1 g, yield 60%) as a white solid. ESI/MS calculated 1-(4-nitrophenyl)piperazine derivative C ₄₈ H ₅₇ N ₈ O ₇ P 888.4, found m / z = 887.6 (M-1).

Example 12

3-(tert-butyldisulfanyl)-2-(isobutoxycarbonylamino)propanoic acid

To S-tert -butylmercapto-L-cysteine (10 g, 47.8 mmol) in _{CH 3} CN (40 mL) was added K ₂ CO ₃ (16.5 g, 119.5 _{mmol) in H 2 O (20 mL).} After stirring for 15 minutes, iso-butylchloroformate (9.4 mL, 72 mmol) was slowly injected. The reaction was carried out for 3 hours. The white solid was filtered through celite and the filtrate was concentrated to remove _{CH 3 CN.} The residue was dissolved in ethyl acetate (200 mL), washed with 1N HCl (40 ml X 3), brine (40 X 1) _{and dried over Na 2} SO ₄ , the desired product ( 2 ) was chromatographed (5% MeOH/ DCM) after

Example 13

tert-Butyl 4-(3-(tert-butyldisulfanyl)-2-(isobutoxycarbonylamino)propanamido)piperidine-1-carboxylate

To the acid (compound 2 from Example 12, 6.98 g, 22.6 mmol) in DMF (50 ml) was added HATU (8.58 g, 22.6 mmol). After 30 min, Hunig base (4.71 ml, 27.1 mmol) and 1-Boc-4-amino piperidine (5.43 g, 27.1 mmol) were added to the mixture. The reaction was stirred at RT for another 3 hours. DMF was removed under high vacuum. The crude residue was dissolved in EtAc (300 _{ml) and washed with H 2} O (50 ml X 3). The final product ( 3 ) was obtained after ISCO purification (5% MeOH/DCM).

Example 14

Isobutyl 3-(tert-butyldisulfanyl)-1-oxo-1-(piperidin-4-ylamino)propan-2-ylcarbamate

30ml of 4M HCl/dioxane was added to compound 3 (7.085g, 18.12mmol) prepared in Example 13. The reaction was completed after 2 hours at room temperature. The HCl salt ( 4 ) was used for the next step without further purification.

Example 15

Isobutyl 3-(tert-butyldisulfanyl)-1-(1-(dichlorophosphoryl)piperidin-4-ylamino)-1-oxopropan-2-ylcarbamate

Compound 4 (7.746g, 18.12mmol) prepared in Example 15 in DCM (200ml) was _{slowly injected with POCl 3} (1.69ml, 18.12mmol) at -78°C under argon _{, and then Et 3} N (7.58ml, 54.36) mmol) was added. The reaction was stirred at room temperature for 5 hours and concentrated to remove excess base and solvent. The product ( 5 ) was provided after ISCO purification (50% EtAc/Hexanes).

Example 16

Isobutyl 3-(tert-butyldisulfanyl)-1-(1-(chloro(((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidine) -1(2H)-yl)-4-tritylmorpholin-2-yl)methoxy)phosphoryl)piperidin-4-ylamino)-1-oxopropan-2-ylcarbamate

1-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione in DCM (100ml) To (moT(Tr)) (5.576 g, 10.98 mmol) was added lutidine (1.92 ml, 16.47 mmol) and DMAP (669 mg, 5.5 mmol) at 0° C., followed by 4 (6.13 g, 12.08 mmol). . The reaction was stirred at room temperature for 18 hours. The desired product ( 6 ) was obtained after ISCO purification (50% EtAc/Hexanes).

Example 17

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyridin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl hexyl (methyl) phosphoramidochloridate

A solution of N-hydroxymethylamine (4.85 ml, 32 mmol) in DCM (80 ml) was cooled at -78 °C under N2. A solution of phosphoryl chloride (2.98 ml, 32 mmol) in DCM (10 ml) was added slowly followed by a solution of Et ₃ N (4.46 ml, 32 mmol) in DCM (10 ml). While stirring is continued, the reaction is allowed to warm to room temperature overnight. The desired product ( 1 ) was obtained as a clear oil after ISCO purification (20% EtAc/Hexanes).

To moT(Tr) (5.10 g, 10.54 mmol) in DCM (100 ml) was added lutidine (3.68 ml, 31.6 mmol) and DMAP (642 mg, 5.27 mmol) at 0° C., followed by 1 (4.89 g, 21.08 mmol) was added. The reaction was stirred at room temperature for 18 hours. The desired product ( 2 ) was obtained after ISCO purification (50% EtOAc/hexanes).

Example 18

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl Dodecyl (methyl) phosphoramidochloridate

The title compound was prepared according to the general procedure described in Examples 6 and 8.

Example 19

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl Morpholino phosphonochloridate

The title compound was prepared according to the general procedure described in Examples 6 and 8.

Example 20

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (S)-2-(Methoxymethyl)pyrrolidin-1-ylphosphonochloridate

The title compound was prepared according to the general procedure described in Examples 6 and 8.

Example 21

((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl 4-(3,4,5-trimethoxybenzamido)piperidin-1-ylphosphonochloridate

To 1-Boc-4-piperidine (1 g, 5 mmol) in DCM (20 ml) was added Hunig base (1.74 ml, 10 mmol), followed by 3,4,5-trimethoxybenzoyl chloride (1.38 g, 6 mmol) added. The reaction was carried out at room temperature for 3 hours and concentrated to remove solvent and excess base. The residue was dissolved in EtAc (100 ml), washed with 0.05N HCl (3 X 15 ml), saturated NaHCO ₃ (2 X 15 ml) and dried over Na ₂ SO ₄ . Product (1) was obtained after ISCO purification (5% MeOH/DCM).

To 7 was added 15 ml of 4N HCl/dioxane, and the reaction was stopped after 4 hours. 8 was obtained as a white solid.

A solution of 8 (1.23 g, 4.18 mmol) in DCM (20 ml) was cooled to -78 °C under _{N 2 .} A solution of phosphoryl chloride (0.39 ml, 4.18 mmol) was added slowly followed by a solution _{of Et 3} N (0.583 ml, 4.18 mmol) in DCM (2 ml). While stirring was continued, the reaction was allowed to warm to room temperature overnight. The desired product ( 9 ) was obtained after ISCO purification (50% EtAc/Hexanes).

To moT(Tr) (1.933 g, 4.0 mmol) in DCM (20 ml) was added lutidine (0.93 ml, 8 mmol) and DMAP (49 mg, 0.4 mmol) at 0° C., followed by 9 (1.647 g, 4 mmol) did The reaction was maintained at room temperature with stirring overnight. The desired product ( 10 ) was obtained after ISCO purification (50% EtAc/Hexanes).

Example 22

Synthesis of cyclophosphoramide-containing subunits ( ^{cp T)}

The moT subunit (25 g) was suspended in DCM (175 ml) and NMI (N-methylimidazole, 5.94 g, 1.4 eq) was added to give a clear solution. Tosyl chloride was added to the reaction mixture and the reaction progress was monitored by TCL until carried out (ca. 1 hour). The aqueous workup was washed with 0.5 M citric acid buffer (pH=5) followed by brine. The organic layer was separated and dried _{over Na 2} SO _{4 .} The solvent was removed by rotary evaporator to give the crude product which was used for the next step without further purification.

The prepared moT tosylate was mixed with propanolamine (1 g/10 ml). The reaction mixture was then placed in an oven at 45° C. overnight and then diluted with DCM (10 ml). Aqueous workup was performed by washing with 0.5 M citric acid buffer (pH=5) followed by brine. The organic layer was separated and dried _{over Na 2} SO _{4 .} The solvent was removed by rotary evaporator to give the crude product. The crude product was analyzed and measured by NMR and HPLC to prepare for the next step without further purification.

The crude product was dissolved in DCM (2.5 ml DCM/g, 1 equiv) and mixed with DIEA (3 equiv). The solution was cooled with dry ice-acetone and POCl ₃ was added dropwise (1.5 eq). The resulting mixture was stirred at room temperature overnight. Aqueous workup was performed by washing with 0.5 M citric acid buffer (pH=5) followed by brine. The organic layer was separated and dried _{over Na 2} SO _{4 .} The solvent was removed on a rotovap to give the product as a yellow solid. The crude product was purified by silica gel chromatography (crude product/silica=1 to 5 ratio, gradient DCM to 50% EA/DCM) and fractions were pooled according to TLC analysis. Removal of the solvent gave the desired product as a mixture of diastereomers. The purified product was analyzed by HPLC (NPP quench) and NMR (H-1 and P-31 ).

Diastereomeric mixtures were analyzed according to the following procedure. The mixture (2.6 g) was dissolved in DCM. This sample was loaded onto a RediSepRf column (80 g normal phase, manufactured by Teledyne Isco) and eluted with 10% EA/DCM to 50% EA/DCM over 20 minutes. Fractions were collected and analyzed by TLC. Fractions were pooled according to TLC analysis and the solvent was removed by rotovap at room temperature. The diastereomeric ratios of the pooled fractions were determined by P-31 NMR and NPP-TFA analysis. If necessary, the procedure was repeated until the diastereoisomer ratio reached 97%.

Example 23

Global cholic acid from PMOplus

A succinimide-activated cholic acid derivative was prepared according to the following procedure. Cholic acid (12 g, 29.4 mmol), N-hydroxysuccinimide (4.0 g, 34.8 mmol), EDCI (5.6 g, 29.3 mmol), and DMAP (1 g, 8.2 mmol) were charged to a round bottom flask. DCM (400 ml) and THF (40 ml) were added to dissolve. The reaction mixture was stirred at room temperature overnight. Water (400 ml) was then added to the reaction mixture, the organic layer was separated and washed with water (2X 400 ml), followed by saturated NaHCO ₃ (300 ml) and brine (300 ml). Then the organic layer was dried over Na ₂ SO ₄ . The solvent was removed by rotary evaporator to give a white solid. The crude product was dissolved in chloroform (100 ml) and precipitated in heptane (1000 ml). The solid was collected by filtration, analyzed by HPLC and NMR and used without further purification.

An appropriate amount of PMOplus (20 mg, 2.8 μmol) was increased into a vial (4 ml) and dissolved in DMSO (500 ul). Activated cholate ester (13 mg, 25 μmol) was added to the reaction mixture according to a ratio of 2 equivalents of active ester per transformation state, and then stirred at room temperature overnight. Reaction progress was determined according to MALDI and HPLC (C-18 or SAX).

After the reaction was complete (as determined by the disappearance of the starting PMOplus), 1 ml of concentrated ammonia was added to the reaction mixture upon completion of the reaction. The reaction vial was then placed in an oven (45° C.) overnight (18 hours), then cooled to room temperature and diluted with 1% ammonia in water (10 ml). This sample was loaded onto an SPE column (2 cm) and the vial was rinsed with 1% ammonia solution (2X 2ml). The SPE column was washed with 1% ammonia in water (3X 6 ml) and the product eluted with 45% acetonitrile in 1% ammonia in water (6 ml). Fractions containing oligomers were identified by UV light density measurement. The product was isolated by lyophilization. Purity and identity were determined by MALDI and HPLC (C-18 and/or SAX).

This same procedure is applicable for ^{deoxycholic acid activation and conjugation to PMO + .}

Example 24

Global guanidinylation of PMOplus

An appropriate amount of PMOplus (25 mg, 2.8 μmol) was increased in a vial (6 ml). 1H-Pyrazole-1-carboxamide chloride (15 mg, 102 μmol) and potassium carbonate (20 mg, 0.15 mmol) were added to a vial. Water was added (500 ul) and the reaction mixture was stirred at room temperature overnight (ca. 18 h). Reaction completion was determined by MALDI.

Upon completion of the reaction, the reaction was diluted with 1% ammonia in water (10 ml) and loaded onto an SPE column (2 cm). The vial was rinsed with 1% ammonia solution (2X 2ml) and the SPE column was washed with 1% ammonia in water (3X 6ml). The product was eluted with 45% acetonitrile in 1% ammonia in water (6ml). Fractions containing oligomers were identified by UV light density measurement. The product was isolated by lyophilization. Purity and identity were determined by MALDI and HPLC (C-18 and/or SAX).

Example 25

Global thioacetyl modification of PMOplus (M23D)

An appropriate amount of PMOplus (20 mg, 2.3 μmol) was added to a vial (4 ml) and dissolved in DMSO (500 ul). N-succinimidyl-S-acetylthioacetate (SATA) (7 mg, 28 μmol) was added to the reaction mixture and stirred at room temperature overnight. Reaction progress was monitored by MALDI and HPLC.

Once complete, 1% ammonia in water was added to the reaction mixture and stirred at room temperature for 2 hours. This solution was loaded onto an SPE column (2 cm). The vial was rinsed with 1% ammonia solution (2X 2ml) and the SPE column was washed with ammonia in water (3X 6ml). The product was washed with 45% acetonitrile in 1% ammonia in water (6 ml). Fractions containing oligomers were identified by UV light density measurement. The product was isolated by lyophilization. Purity and identity were determined by MALDI and HPLC (C-18 and/or SAX).

Example 26

Global Succinic Acid Modification of PMOplus

An appropriate amount of PMOplus (32 mg, 3.7 μmol) was added to a vial (4 ml) and dissolved in DMSO (500 ul). N-ethyl morpholino (12 mg, 100 μmol) and succinic anhydride (10 mg, 100 μmol) were added to the reaction mixture and allowed to warm at room temperature overnight. Reaction progress was monitored by MALDI and HPLC.

Once complete, 1% ammonia in water was added to the reaction mixture and stirred at room temperature for 2 hours. This solution was loaded onto an SPE column (2 cm). The vial was rinsed with 1% ammonia solution (2X 2ml) and the SPE column was washed with 1% ammonia in water (3X 6ml). The product was eluted with 45% acetonitrile in 1% ammonia in water (6ml). Fractions containing oligomers were identified by UV light density measurement. The product was isolated by lyophilization. Purity and identity were determined by MALDI and HPLC (C-18 and/or SAX).

The above procedure is likewise applicable to the modification of glutaric acid (glutaric anhydride) and tetramethyleneglutaric acid (tetramethyleneglutaric anhydride) of PMOplus.

Example 27

Preparation of Oligonucleotide Analogs Containing Modified End Groups

To a solution of 25-mer PMO containing the free 3'-end (27.7 mg, 3.226 μmol) in DMSO (300 μl) farnesyl bromide (1.75 μl, 6.452 μmol) and diisopropylethylamine (2.24 μl, 12.9 μmol) ) was added. The reaction mixture was stirred at room temperature for 5 hours. The crude reaction mixture was diluted with 10 mL of 1% aqueous NH ₄ OH and then loaded onto a 2 mL Amberchrome CG300M column. The column was then rinsed with 3 column volumes of water and the product eluted with 6 mL of 1:1 acetonitrile and water (v/v). The solution was then lyophilized to give the title compound as a white solid.

Example 28

Preparation of morpholino oligomers

Preparation of trityl piperazine phenyl carbamate 35 (see Figure 3): To a cooled solution of compound 11 in dichloromethane (6 mL/g 11) potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate) solution was added. To this two-step mixture was slowly added a solution of phenyl chloroformate (1.03 equiv) in dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20°C. At the end of the reaction ((1-2 hours), the layers were separated. The organic layer was washed with water and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. Yield = 80%.

Preparation of carbamate alcohol 36: Sodium hydride (1.2 eq) was suspended in 1-methyl-2-pyrrolidinone (32 mL/g sodium hydride). To this suspension were added triethylene glycol (10.0 equiv) and compound 35 (1.0 equiv). The resulting slurry was heated to 95°C. At the end of the reaction (1-2 hours), the mixture was cooled to 20°C. To this mixture was added 30% dichloromethane/methyl tert-butyl ether (v:v) and water. The product-containing organic layer was washed successively with aqueous NaOH, aqueous succinic acid, and saturated aqueous sodium chloride. Product 36 was isolated by crystallization from dichloromethane/methyl tert-butyl ether/heptane. Yield = 90%.

Preparation of tail acid 37: To a solution of compound 36 in tetrahydrofuran (7 mL/g 36) was added succinic anhydride (2.0 equiv) and DMAP (0.5 equiv). The mixture was heated to 50 °C. At the end of the reaction (5 hours), the mixture was cooled to 20° C. and adjusted to pH 8.5 with aqueous NaHCO 3 . Methyl tert-butyl ether was added and the product was extracted into the aqueous layer. Dichloromethane was added and the mixture was adjusted to pH 3 with aqueous citric acid. The product-containing organic layer was washed with a mixture of pH=3 citrate buffer and saturated aqueous sodium chloride. This dichloromethane solution of 37 was used without isolation in the preparation of compound 38.

Preparation of 38: To a solution of compound 37 N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) (1.02 equiv), 4-dimethylaminopyridine (DMAP) (0.34 equiv) , and 1-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) (1.1 equiv). The mixture was heated to 55°C. Upon completion of the reaction (4-5 hours), the mixture was cooled to 20° C. and washed successively with 1:1 0.2 M citric acid/brine and brine. The dichloromethane solution was subjected to solvent exchange with acetone followed by N,N-dimethylformamide and the product was isolated by precipitation from acetone/N,N-dimethylformamide in saturated aqueous sodium chloride. The crude product was reslurried several times in water to remove residual N,N-dimethylformamide and salts. Yield of 38 from compound 36=70%. Introduction of the activation tail on the disulfide anchor resin was performed in NMP by the procedure used for introduction of subunits during solid phase synthesis.

Preparation of a solid support for the synthesis of morpholino oligomers:

This procedure was performed in a silanized, jacketed peptide vessel (customized by ChemGlass, NJ, USA) with a landscaped porous (40-60 μm) glass frit, overhead stirrer, and 3-way Teflon stopcock for frit or vacuum extraction. N2 was bubbled through. Temperature control was carried out in the reaction vessel by means of a circulating water bath.

The resin treatment/washing step in the following procedure consists of two basic operations: resin fluidization and solvent/solution extraction. For resin fluidization, a stopcock is positioned to flow N2 through the frit and specified resin treatment/wash, add to the reactor, and permeate to fully wet the resin. Mixing was then started and the resin slurry was mixed for the specified time. For solvent/solution extraction, stop mixing and N2 flow, start the vacuum pump and position the stopcock to dispose/wash the resin to drain the residue. All resining/washing volumes were 15 mL/g of resin unless otherwise indicated.

1-Methyl-2-pyrrolyl to aminomethylpolystyrene resin (100-200 mesh; ˜1.0 mmol/g N2 substitution; 75 g, 1 eq, Polymer Labs, UK, part #1464-X799) in a silanized jacketed peptide container. Don (NMP; 20 ml/g resin) was added and the resin swelled with mixing for 1-2 hours. After draining the swollen solvent, the resin was washed with 25% isopropanol/dichloromethane (2 x 3-4 min) and dichloromethane (2 x 1-2 min). After draining the final wash, the resin was fluidized with a solution of disulfide anchor 34 in 1-methyl-2-pyrrolidinone (0.17 M; 15 mL/g resin, ˜2.5 equiv) and the resin/reagent mixture was heated at 45° C. to 60° C. heated for hours. Upon completion of the reaction, the heating was stopped, the anchor solution was drained, and the resin was washed with 1-methyl-2-pyrrolidinone (4 x 3-4 min) and dichloromethane (6 x 1-2 min). The resin was treated with a solution of 10% (v/v) diethyl dicarbonate in dichloromethane (16 mL/g; 2 x 5-6 min) and then washed with dichloromethane (6 x 1-2 min). Resin 39 (see FIG. 4 ) was dried to constant weight (±2%) under N2 flow for 1-3 hours and then under vacuum. Yield of original resin weight: 110-150%.

Determination of the loading of aminomethylpolystyrene-disulfide resin:

The loading of the resin (number of potentially available reactive moieties) was determined by spectrometric analysis for the number of triphenylmethyl per gram of resin.

A known weight of dry resin (25±3 mg) was transferred to a silanized 25 ml volumetric flask and ˜5 mL of 2% (v/v) trifluoroacetic acid in dichloromethane was added. The contents were mixed with gentle agitation and then allowed to stand for 30 minutes. The volume was raised to 25 mL with an additional 2% (v/v) trifluoroacetic acid in dichloromethane and the contents were mixed thoroughly.

An aliquot of the trityl-containing solution (500 μl) was transferred to a 10 mL volumetric flask using a positive displacement pipette and the volume was raised to 10 mL with methanesulfonic acid.

The trityl cation content in the final solution was determined by UV absorption at 431.7 nm and the resin loading was calculated using the appropriate volume, dilution, extinction coefficient (ε: 41 μmol-1 cm-1) and resin weight to determine trityl groups per gram resin (μmol /g). The analysis was performed in triplicate and the average load was calculated.

The resin loading in this example provides a loading of approximately 500 μmol/g to the resin. Loads of 300-400 μmol/g were obtained when the disulfide anchor introduction step was carried out at room temperature for 24 hours.

Tail loading: Using the same set-up and volume for the preparation of aminomethylpolystyrene-disulfide resin, the tail can be introduced into the molecule. For the coupling step, a solution of 38 (0.2 M) in 4-ethylmorpholine containing NMP (NEM, 0.4 M) was used instead of the disulfide anchor solution. After 2 hours at 45° C., Resin 39 was washed twice with 5% diisopropylethylamine in 25% isopropanol/dichloromethane and once with DCM. To the resin was added a solution of benzoic anhydride (0.4 M) and NEM (0.4 M). After 25 min the reaction jacket was cooled to room temperature and the resin was washed twice with 5% diisopropylethylamine in 25% isopropanol/dichloromethane and once with DCM. Resin 40 was filtered and dried under high vacuum. The load on resin 40 is defined as that of the original aminomethylpolystyrene-disulfide resin 39 used in the tail load.

Solid Phase Synthesis: Morpholino oligomers were prepared on a Gilson AMS-422 automated peptide synthesizer in a 2 mL Gilson polypropylene reaction column (Part # 3980270). Aluminum blocks with channels for water flow are placed around the column as they are fixed on the synthesizer. The AMS-422 adds reagent/wash solutions alternately, holds for a specified time, and evacuates the column using vacuum.

For oligomers ranging in length up to about 25 subunits, aminomethylpolystyrene-disulfide resins with a loading of around 500 μmol/g of resin are preferred. For larger oligomers. Aminomethylpolystyrene-disulfide resins with a loading of 300-400 μmol/g of resin are preferred. If a molecule with a 5'-tail is desired, the tail loaded resin is chosen with the same loading guidelines.

The following reagent solutions were prepared:

Detritylation solution: 10% cyanoacetic acid (w/v) in 4:1 dichloromethane/acetonitrile; Neutralization solution: 5% diisopropylethylamine in 3:1 dichloromethane/isopropanol; Coupling solution: 0.18 M (or 0.24 M for oligomers grown longer than 20 subunits) activated morpholino subunit of the desired base and bond type, and 0.4 M N ethyl morpholine in 1,3-dimethylimidazolidinone. Dichloromethane (DCM) was used as an intermediate wash separating the different reagent solution washes.

On the synthesizer, using a block fixed at 42° C., add 2 mL of 1-methyl-2-pyrrolidinone to each column containing 30 mg of aminomethylpolystyrene-disulfide resin (or tail resin) and place at room temperature. incubated for 30 min. After washing twice with 2 mL of dichloromethane, the following synthesis cycle was used:

Step Volume Delivery Duration

Detritylation 1.5 mL Manifold 15 Seconds

Detritylation 1.5 mL Manifold 15 Seconds

Detritylation 1.5 mL Manifold 15 Seconds

Detritylation 1.5 mL Manifold 15 Seconds

Detritylation 1.5 mL Manifold 15 Seconds

Detritylation 1.5 mL Manifold 15 Seconds

DCM 1.5 mL Manifold 30 sec

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

DCM 1.5 mL Manifold 30 sec

Coupling 350 uL-500 uL Syringe 40 min

DCM 1.5 mL Manifold 30 sec

Neutralize 1.5 mL Manifold 30 Seconds

Neutralize 1.5 mL Manifold 30 Seconds

DCM 1.5 mL Manifold 30 sec

DCM 1.5 mL Manifold 30 sec

DCM 1.5 mL Manifold 30 sec

The sequences of the individual oligomers were programmed in the synthesizer so that each column received the appropriate coupling solution (A,C,G,T,I) in the appropriate sequence. The column was removed from the block when the oligomer in the column had completed introduction of its final subunit and the final cycle consisted of a couple of 4-methoxytriphenylmethyl chloride (0.32 M in DMI) containing 0.89M 4-ethylmorpholine. This was done manually with the ring solution.

Cleavage from resin and removal of base and backbone protecting groups: After methoxytritylation, the resin was washed 8 times with 2 mL 1-methyl-2-pyrrolidinone. 1 mL of a cleavage solution consisting of 0.1 M 1,4-dithiopreitol (DTT) and 0.73 M triethylamine in 1-methyll-2-pyrrolidinone is added, the column is capped, and 30 min at room temperature. politicized while Afterwards, the solution was drained into a 12 mL Wheaton vial. The heavily shrunken resin was washed twice with 300 μl of cleavage solution. To the solution was added 4.0 mL concentrated aqueous ammonia (stored at -20°C), the vial was capped tightly (with a Teflon line screw cap), and the mixture was stirred to mix the solution. Cleavage of base and backbone protecting groups was performed by placing the vial in an oven at 45° C. for 16-24 hours.

Initial oligomer separation: The vial ammonolysis solution was removed from the oven and cooled to room temperature. The solution was diluted with 20 mL of 0.28% aqueous ammonia and passed through a 2.5x10 cm column containing Macroprep HQ resin (BioRad). A salt gradient (A: 0.28% ammonia with B: 1 M sodium chloride in 0.28% ammonia; 0-100% B 60 min) was used to elute the methoxytrityl containing peak. The bound fractions were pooled and further processed according to the desired product.

Demethoxytritylation of Morpholino Oligomers: The pooled fractions from Macroprep purification were treated with 1 M H3PO4 to lower the pH to 2.5. After initial mixing, the samples were allowed to stand at room temperature for 4 minutes, at which time they were neutralized to pH 10-11 with 2.8% ammonia/water. The product was purified by solid phase extraction (SPE).

Amberchrome CG-300M (Rohm and Haas; Philadelphia, PA) (3 mL) was packed in a 20 mL fritted column (BioRad Econo-Pac Chromatography Columns (732-1011)) and the resin was rinsed with 3 mL of the following reagent: 0.28% NHOH/80% acetonitrile; 0.5M NaOH/20% ethanol; water; 50 mM H3PO4/80% acetonitrile; water; 0.5 NaOH/20% ethanol; water; 0.28% NH4OH.

The solution from demethoxytritylation was loaded onto the column and the resin was rinsed three times with 3-6 mL 0.28% aqueous ammonia. A Wheaton vial (12 mL) was placed on the column and the product was eluted with two washes with 2 mL of 45% acetonitrile in 0.28% aqueous ammonia. The solution was frozen on dry ice and the vial was placed in a freeze dryer to yield a fluffy white powder. The sample is dissolved in water, filtered through a 0.22 micron filter (Pall Life Sciences, Acrodisc 25 mm syringe filter, with 0.2 micron HT Tuffryn membrane) using a syringe and the optical density (OD) measured on a UV spectrometer to determine the oligomers present. The OD units of as well as the variance samples for analysis were determined. The solution was then returned to the Wheaton vial for lyophilization.

Analysis of morpholino oligomers: A MALDI-TOF mass spectrometer is used to determine the composition of the fractions in purification as well as provide evidence for the identity (molecular weight) of the oligomers. Samples were prepared using 3,5-dimethoxy-4-hydroxycinnamic acid (cinnaphinic acid), 3,4,5-trihydroxyacetophenone (THAP) or alpha-cyano-4-hydroxycinnamic acid (HCCA) as a matrix. ) after dilution using the solution.

Cation exchange (SCX) HPLC is 25 mM pH=5 sodium acetate 25% acetonitrile (buffer A) and 25 mM pH=5 sodium acetate 25% acetonitrile 1.5 M potassium chloride (buffer B) (gradient 10-100% B in 15) min) or 25 mM KH2PO4 25% acetonitrile at pH=3.5 (buffer A) and 25 mM KH2PO4 25% acetonitrile at pH 3.5 with 1.5 M potassium chloride (buffer B) (gradient 0-35% B in 15 min) This was performed using a used Dionex ProPac SCX-10, 4x250 mm column (Dionex Corporation; Sunnyvale, CA). The former system was used for positively charged oligomers with no peptide attached, while the latter system was used for peptide conjugates.

Purification of morpholino oligomers by cation exchange chromatography:

Samples were dissolved in 20 mM sodium acetate, pH=4.5 (buffer A) and applied to a source 30 cation exchange resin column (GE Healthcare) and 0.5 M in 20 mM sodium acetate and 40% acetonitrile, pH=4.5 (buffer B) Eluted with a gradient of sodium chloride. The pooled fractions containing the product were neutralized with concentrated aqueous ammonia and applied to an Amberchrome SPE column. The product was eluted, frozen and lyophilized as above.

Example 29

Preparation of Exemplary Conjugates

The peptide sequence AcR ₆ G was prepared according to standard peptide synthesis methods known in the art. PMO (NG-05-0225, 3'-H: M23D: 5'-EG3, sequence for binding to exon 23 of mdx mice, 350 mg, 1 eq), AcR6G (142 mg, 2) in DMSO (3 mL) eq), to a solution of HATU (31 mg, 2 equiv) was added diisopropylethylamine (36 μl, 5 equiv) at room temperature. After 1 h, the reaction was worked up and the desired peptide-oligomer conjugate was subjected to SCX chromatography (A: 20 mM NaH2PO4 in 25% acetonitrile/H2O, pH 7.0; B: 1.5 M guanidine HCl in 25% acetonitrile/H2O and 20 eluted with a gradient of mM NaH2PO4, pH 7.0). The bound fractions were subjected to solid phase extraction (1M NaCl followed by water elution). The conjugate was obtained as a white powder (257 mg, yield 65.5%) after lyophilization.

Example 30

Treatment of MDX Mice of Exemplary Conjugates of the Invention

The MDX mouse is an acceptable and well-characterized animal model for Duchenne muscular dystrophy (DMD) containing a mutation in exon 23 of the dystrophin gene. The M23D antisense sequence (SEQ ID NO: 15) is known to induce exon 23 skipping and restoration of a functional dystrophinic expression. MDX mice were dosed once (50 mg/kg) by tail vein gaze with one of the following conjugates:

1. 5'-EG3-M23D-BX(RXRRBR) ₂ (AVI5225);

2. 5'-EG3-M23D-G(R) ₅ (NG-11-0045);

3. 5'-EG3-M23D-G(R) ₆ (NG-11-0009);

4. 5'-EG3-M23D-G(R) ₇ (NG-11-0010); or

5. 5'-EG3-M23D-G(R) ₈ (NG-11-0216)

wherein M23D is a morpholine oligonucleotide having the sequence GGCCAAACCTCGGCTTACCTGAAAT and "EG3" has the following structure (XXIX) linked to the 5' end of the oligomer via a peptide linker:

One week after injection, MDX mice were sacrificed and RNA was extracted from various muscle tissues. Endpoint PCR was used to determine the relative abundance of mRNA without exon 23 and dystrophin mRNA containing exon 23 due to antisense-induced exon skipping. Percent exon 23 skipping is a measure of antisense activity in vivo. 5 and 6 show the results from quadriceps (QC, FIGS. 5A and 6A), diaphragm (DT, FIGS. 5B and 6B) and heart (HT, FIGS. 5C and 6C) after one week of treatment, respectively. The dose response between AVI-5225 and other conjugates was similar. Among the arginine families, the R ₆ G peptide had the highest efficacy in quadriceps and diaphragm and was similar to other arginine families in the heart.

Example 31

BUN Levels and Survival of Mice Treated with Exemplary Conjugates

Mice were treated with the conjugates described in Example 30, and KIM-1 levels, BUN levels and survival rates were measured according to the general procedures described in Example 32 below and known in the art. Surprisingly, Figure 7A shows that all glycine-binding conjugates had significantly lower BUN levels than the XB-binding conjugates (AVI-5225). In addition, mice treated with the glycine-binding conjugate survived longer at the higher dose than the XB-binding conjugate ( FIG. 7B ), and the R ₈ G conjugate is minimally resistant to the arginine polymer. All mice treated with R ₆ G conjugate (NG-11-0009) survived doses up to 400 mg/kg (data not shown).

KIM-1 (FIG. 8A) and clustererin (FIG. 8B) of mice treated with the glycine binding conjugate were significantly lower than mice treated with AVI-5225. These data indicate that the conjugates of the present invention have lower toxicity than the prior art conjugates, and the efficacy of the conjugates is not reduced as shown above in Example 30. Thus, this conjugate has a better therapeutic window than other known conjugates and is also a potentially better drug candidate.

Example 32

Toxicology of Exemplary Conjugates

Four exemplary conjugates of the invention were tested for their toxicology in mice. The conjugates were as follows:

1. 5'-EG3-M23D-BX(RXRRBR) ₂ (AVI5225);

2. 5'-EG3-M23D-G(RXRRBR) ₂ (NG-11-0654);

3. 5'-EG3-M23D-BX(R) ₆ (NG-11-0634); and

4. 5'-EG3-M23D-G(R) ₆ (NG-11-0009)

wherein M23D is a morpholino oligonucleotide having the sequence GGCCAAACCTCGGCTTACCTGAAAT and "EG3" is linked to the 5' end of the oligomer via a piperazine linker having the following structure (i.e. structure XXIX):

8 week old male mice (C57/BL6; Jackson Laboratories, 18-22 grams) were treated with the conjugate formulated in saline. Mice were acclimated for a minimum of 5 days prior to initiation of experimental procedures.

Animals were housed up to 3 per cage in clear polycarbonate microisolator cages with certified contact bedding. Cages were identified with standards described in the Animal Care Act (including all amendments) and the Guide to the Care and Use of Laboratory Animals, National Academy Press, Washington, D.C., 2010.

Animals were randomly ordered into treatment groups based on cage weights specified in the table below. Group assignments were documented as test records.

Table 8. Toxicology Study Design

The administration date for this test was designated as test day 1. The conjugate was administered to the tail vein as a slow push mass (~5 sec). All animals were dosed over two days. Groups 1 to 8 were administered on the first day and groups 9 to 16 were administered on the second day. Treatment groups (TG) 13-16 were administered according to the table below. Results from these TGs did not affect the progression of other TGs. The first 2 TGs of each conjugate were administered according to the table above. When all animals died in the 100 mg/kg group, the remaining TG of the test article was not administered and the test was ended. At least one animal survived 2 hours after administration in the 100 mg/kg group, followed by administration in the 150 mg/kg group. Next, when all animals died in the 150 mg/kg group, the remaining TG of the test article was not administered and the test was ended. At least one animal survived 2 hours after administration in the 150 mg/kg group, followed by administration in the 200 mg/kg group.

Animals were observed for moribund and mortality once daily. Any animals showing signs of distress were humanely comforted according to Numira Bioscience standard handling procedures, especially when death was imminent. Body weights were recorded on arrival, administration and necropsy. Detailed clinical observations were made and recorded after administration at 0 min, 15 min and 2 hours to evaluate the tolerability of administration.

Blood samples (maximum volume, approx. 1 mL) were obtained from all animals via cardiac puncture after dosing 3 days before necropsy. Blood samples were collected in red top microtainer tubes and maintained at room temperature for 30 minutes but within 10 minutes prior to centrifugation. Samples were centrifuged at approximately 1500-2500 rpm for 15-20 minutes to obtain serum.

Animals unlikely to survive until the next planned observation were increased and euthanized. Animals found to be dead were escalated and the time of death was assessed as closely as possible. Blood and tissue samples were not collected.

On day 3 (2 days post-dose), all animals were humanely euthanized with carbon dioxide. Euthanasia was performed in June 2007 according to the approved American Veterinary Medical Association (AVMA) guidelines for euthanasia.

A partial full autopsy included examination and documentation of findings. All external surfaces and holes were evaluated. All abnormalities observed during tissue collection were fully described and recorded. No further organization was taken.

Right and left kidneys were collected. Tissues were collected within 15 min or less of euthanasia. All instruments and tools used varied between treatment groups. All tissues were flash frozen and stored at <-70°C as soon as possible after collection.

Kidney damage markers were obtained as follows. RNA from mouse kidney tissue was purified using Quick Gene Mini80 Tissue Kit SII (Fujifilm). Briefly, approximately 40 mg of tissue was added to 0.5 ml lysis buffer (5 μl 2-mercaptoethanol in 0.5 ml lysis buffer) in a MagnaLyser green bead vial (Roche), 2 sets of 3x 3800 RPM and 3 sets of 1x Homogenization was performed using a MagNA Lyser (Roche) with 6500 RPM. Samples were cooled in 3-4 min between each low speed set and between each high speed run. The homogenate was centrifuged for 5 min at 400 x g at room temperature. Homogenates were immediately processed for RNA purification according to the Quick Gene Mini80 protocol. Samples were subjected to on-column DNA digestion with DNase I (Qiagen) for 5 minutes. Total RNA was quantified with a NanoDrop 2000 spectrometer (Thermo Scientific).

qRT-PCR was performed using Applied Bioscience reagents (one-step RT-PCR), and primer/probe sets (ACTB, GAPDH, KIM-1, Clusterin-FAM reporters) were pre-designed.

Each reaction contained (30 ul total):

15ul 2x qRT-PCR Buffer from ABI One-Step Kit

1.5ul Primer/Probe Mix

8.75 ul nuclease-free water

0.75ul 40x Multiscript + RNase Inhibitor

4 ul RNA template (100 ng/ul)

The qRT one-step program was performed as follows:

1. 48C for 30 minutes

2. 95C for 10 minutes

3. 95C for 15 seconds

4. 60C for 1 minute

5. Repeat steps 3-4 39 times for a total of 40 cycles

Samples were run in 3 wells and averaged for further analysis. Analysis was performed using the ΔΔCt method. Briefly, the experimental ΔCt [Ct(target) - Ct(reference)] was subtracted by the control ΔCt [Ct(target) - Ct(reference)]=ΔΔCt. The fold change range was calculated as follows: 2^-(ΔΔCt+SD) to 2^-(ΔΔCt-SD). Control = excipient treated animal group (pooled), target = KIM-1; Reference=GAPDH; SD= Sqrt[(SD target^2)+(SDref^2)].

The results of the KIM data are shown in FIG. 10 . Conjugates comprising a carrier peptide with terminal glycine have a low KIM concentration with the lowest _{R 6 G peptide.} The presence of terminal G and the unnatural amino acid (aminohexanoic acid) appears to play a role in the toxicity of the conjugate.

Frozen serum samples were sent on dry ice to the IDEXX laboratory (West Sacramento, CA) for processing. Serum dilutions were performed according to IDEXX standard processing procedures (SOPs) as needed. Blood chemistry results were analyzed. The hematuria nitrogen levels are shown in FIG. 11 . Again, the G-linked conjugates had low BUN levels and also the terminal G and the entire peptide sequence appear to play a role in the toxicological profile of the conjugate.

Kidney tissue (approximately 150 mg) was precisely weighed into a 2 mL screw cap vial partially filled with ceramic beads. 5 volumes Tissue PE LB buffer (G Biosciences) containing 10 U/mL protease K (Sigma) was added to 1 part tissue. Samples were homogenized with a Roche MagnaLyser (4×40 sec @ 7,000 rpm, cooling between runs) and incubated at 40° C. for 30 minutes. If necessary, tissue homogenates were diluted with BSAsal (3 mg/mL BSA + 20 mM NaCl) to bring high sample concentrations within the calibration range.

Calibration samples were prepared by spiking a solution of 3 mg/mL BSA in 20 mM NaCl using a known amount of an appropriate analytical reference standard. Two sets of eight samples were prepared each. The ULOQ was 40 μg/mL and the LLOQ was 0.065536 μg/mL. An internal standard (NG-07-0775) was added to all samples with the exception of some blank samples designated as double blanks (no drug, no internal standard). Samples were extracted by agitating 100 μL aliquots with 3 volumes of methanol.

After centrifugation (15 min, 14,000 rpm), the supernatant was transferred to a new tube and dried in a Speedvac. The dried sample was reconstituted with an appropriate amount of FDNA (5' d FAM-ATTTCAGGTAAGCCGAGGTTTGGCC 3') in [10 mM Tris pH 8.0 + 1 mM EDTA + 100 mM NaCl]-acetonitrile (75-25).

Samples were run on a Dionex UltiMate 3000 HPLC using anion exchange chromatography (Dionex DNAPac 4x250 mm column). The injection volume was 5 μL. The mobile phase consisted of a gradient of increasing NaCl concentrations and 80% water containing 20% acetonitrile and 25 mM Tris pH 8.0. The flow rate was 1 mL/min, and the number of runs was 10 minutes per sample. Fluorescence detectors were fixed at EX 494 nm and EM 520 nm. Peak identification was based on retention time. The peak height ratio (analyte:internal standard) was used for quantification. Calibration curves were calculated based on the mean response factors of two checkpoint samples (one set run at the beginning of the batch, and the other set run at the end of the batch). A linear curve fitted to the 1/x basis weight factor was used. A blank sample (check sample without addition of reference compound) and two blank samples (internal standard added) were used to ensure assay specificity and absence of residues.

Figure 12 shows that kidney concentrations are similar among the tested conjugates.

The data show that the conjugates of the present invention have similar efficacy and improved toxicity compared to other conjugates. 9A-D _{summarize these results for the R 6} G conjugate (NG-11-0009).

The various embodiments described above can be combined to provide further embodiments. All US patents, US patent application publications, foreign patents, foreign patent applications, and non-patent publications cited herein and/or listed in application data sheets are hereby incorporated by reference in their entirety. Aspects of the embodiments may be modified as necessary to utilize the concepts of various patents, applications, and publications to provide still further embodiments. These and other changes to the embodiment can be made in view of the above detailed description. In general, the terms used in the following claims are not to be construed as limiting the claims to the specific embodiments set forth herein and in the claims, but should It should be construed as including all possible embodiments together. Accordingly, the claims are not limited to the technical content.

SEQUENCE LISTING <110> AVI BioPharma, Inc. Hanson, Gunnar <120> PEPTIDE OLIGONUCLEOTIDE CONJUGATES <130> 120178.495PC <140> PCT/US2011/061282 <141> 2011-11-17 <150> US 13/101,942 <151> 2011-05-05 <150> US 13/107,528 <151> 2011-05-13 <160> 575 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 1 cggtccacgt agactaacaa ct 22 <210> 2 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 2 gaagttcaca cagataaact tct 23 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 3 cggttagaag actcatcttt 20 <210> 4 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 4 tttcgacatc ggttagaaga ctcat 25 <210> 5 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 5 gagacgccat gatgtggatg tc 22 <210> 6 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 6 gaaacacgga cacccaaagt agt 23 <210> 7 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 7 tcccagcgtc aatatgctgt tt 22 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 8 gcctaggatc cacggtgcgc 20 <210> 9 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 9 gggacaaaat ggatcccatt attaatggaa attctgctaa 40 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 10 taatgggatc cattttgtcc c 21 <210> 11 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 11 aataatggga tccattttgt ccc 23 <210> 12 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 12 cattaataat gggatccatt ttgtccc 27 <210> 13 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 13 gaatttccat taataatggg atccattttg 30 <210> 14 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 14 cagaatttcc attaataatg ggatccatt 29 <210> 15 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 15 ggccaaacct cggcttacct gaaat 25 <210> 16 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 16 ggccaaacct cggcttacct gaaat 25 <210> 17 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 17 gctattacct taacccag 18 <210> 18 <211> 52 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 18 gaaaaaagat tatattgatt ttaaaatcat gcaaaaactg caactctgtg tt 52 <210> 19 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 19 catacattg cagtttttgc atcat 25 <210> 20 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 20 tcatttttaa aaatcagcac aatctt 26 <210> 21 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 21 cagtttttgc atcattttta aaaatc 26 <210> 22 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 22 gatctgtcaa atcgcctgca ggtaa 25 <210> 23 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 23 aaactgttca gcttctgtta gccac 25 <210> 24 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 24 ttgtgtcttt ctgagaaact gttca 25 <210> 25 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 25 ctgacaacag tttgccgctg cccaa 25 <210> 26 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 26 ccaatgccat cctggagttc ctgtaa 26 <210> 27 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 27 cattcaatgt tctgacaaca gtttgccgct 30 <210> 28 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 28 cttacaggct ccaatagtgg tcagt 25 <210> 29 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 29 ccactcagag ctcagatctt ctaacttcc 29 <210> 30 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 30 gggatccagt atacttacag gctcc 25 <210> 31 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 31 acatcaagga agatggcatt tctagtttgg 30 <210> 32 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 32 ctccaacatc aaggaagatg gcatttctag 30 <210> 33 <211> 26 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 33 gagcaggtac ctccaacatc aaggaa 26 <210> 34 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 34 ctgaaggtgt tcttgtactt catcc 25 <210> 35 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 35 tgttcttgta cttcatccca ctgattctga 30 <210> 36 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 36 ctttcataat gctggcag 18 <210> 37 <211> 14 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 37 cataatgctg gcag 14 <210> 38 <211> 8 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 38 gctggcag 8 <210> 39 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 39 cagcagcag 9 <210> 40 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 40 cagcagcagc ag 12 <210> 41 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 41 cagcagcagc agcag 15 <210> 42 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 42 cagcagcagc agcagcag 18 <210> 43 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 43 age 9 <210> 44 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 44 agcagcagca gc 12 <210> 45 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 45 agcagcagca gcagc 15 <210> 46 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 46 agcagcagca gcagcagc 18 <210> 47 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 47 gcagcagca 9 <210> 48 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 48 gcagcagcag ca 12 <210> 49 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 49 gcagcagcag cagca 15 <210> 50 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 50 gcagcagcag cagcagca 18 <210> 51 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 51 agcagcagca gcagcagcag cagca 25 <210> 52 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 52 cagcagcagc agcagcagca gcagc 25 <210> 53 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 53 caggcaggc 9 <210> 54 <211> 12 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 54 caggcaggca gg 12 <210> 55 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Antisense oligomer <400> 55 caggcaggca ggcaggcagg cagg 24 <210> 56 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 56 Arg Arg Arg Gin Arg Arg Lys Lys Arg 1 5 <210> 57 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 57 Arg Lys Lys Arg Arg Gin Arg Arg Arg 1 5 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 58 Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe 1 5 10 <210> 59 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 59 Arg Arg Arg Arg Arg Phe Phe Arg Arg Arg Arg 1 5 10 <210> 60 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 60 Arg Arg Arg Arg One <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 61 Arg Arg Arg Arg Arg 1 5 <210> 62 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 62 Arg Arg Arg Arg Arg Arg 1 5 <210> 63 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 63 Arg Arg Arg Arg Arg Arg Arg 1 5 <210> 64 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 64 Arg Arg Arg Arg Arg Arg Arg Arg 1 5 <210> 65 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 65 Arg Arg Arg Arg Arg Arg Arg Arg Arg 1 5 <210> 66 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = Acp <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg 66 1 5 10 <210> 67 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 14 <223> Xaa = Acp <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg 67 1 5 10 15 <210> 68 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = Acp <220> <221> MOD_RES <222> 5, 11 <223> Xaa = bAla <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg 68 1 5 10 <210> 69 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> Arg Ala Arg Arg Ala Arg Arg Ala Arg Arg Ala Arg Phe Phe Cys 69 1 5 10 15 <210> 70 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> Arg Gly Arg Arg Gly Arg Arg Gly Arg Arg Gly Arg Phe Phe Cys 70 1 5 10 15 <210> 71 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 71 Arg Arg Arg Gin Arg Arg Lys Lys Arg Cys 1 5 10 <210> 72 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 72 Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Cys 1 5 10 <210> 73 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 3, 6, 9, 12 <223> Xaa = Acp <220> <221> MOD_RES <222> 13 <223> Xaa = bAla <400> 73 Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Xaa 1 5 10 <210> 74 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 13 <223> Xaa = Acp <220> <221> MOD_RES <222> 14 <223> Xaa = bAla <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Xaa 74 1 5 10 <210> 75 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1, 4, 7, 10, 13 <223> Xaa = Acp <220> <221> MOD_RES <222> 14 <223> Xaa = bAla <400> Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Xaa 75 1 5 10 <210> 76 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10, 12 <223> Xaa = Acp <220> <221> MOD_RES <222> 13 <223> Xaa = bAla <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Xaa 76 1 5 10 <210> 77 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10, 12, 14 <223> Xaa = Acp <220> <221> MOD_RES <222> 15 <223> Xaa = bAla <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Xaa 77 1 5 10 15 <210> 78 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 14, 16 <223> Xaa = Acp <220> <221> MOD_RES <222> 17 <223> Xaa = bAla <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 78 1 5 10 15 Xaa <210> 79 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 13 <223> Xaa = Acp <220> <221> MOD_RES <222> 5, 11, 14 <223> Xaa = bAla <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Xaa 79 1 5 10 <210> 80 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 80 Arg Arg Arg Arg Arg Arg Gly 1 5 <210> 81 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 81 Arg Arg Arg Arg Arg Arg Arg Arg Gly 1 5 <210> 82 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 82 Arg Arg Arg Arg Arg Arg Arg Arg Arg Gly 1 5 <210> 83 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> Arg Arg Arg Arg Arg Gly Arg Arg Arg Arg Gly 83 1 5 10 <210> 84 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 84 Arg Arg Arg Arg Arg Phe Phe Arg Arg Arg Arg Arg Gly 1 5 10 <210> 85 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 85 Arg Lys Lys Arg Arg Gin Arg Arg Arg Gly 1 5 10 <210> 86 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <400> 86 Arg Arg Arg Gin Arg Arg Lys Lys Arg Gly 1 5 10 <210> 87 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> VARIANT <222> 2, 8 <223> Xaa = Ala, Thr, Phe, beta-alanine, Val, Leu, lie, Ser, Gly, Trp, and 6-aminohexanoic acid <400> Arg Xaa Arg Arg Gly Gly Arg Xaa Arg Arg Gly Gly 87 1 5 10 <210> 88 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> VARIANT <222> 2, 6, 8, 12 <223> Xaa = Ala, Thr, Phe, beta-alanine, Val, Leu, lie, Ser, Gly, Trp, and 6-aminohexanoic acid <400> Arg Xaa Arg Arg Arg Xaa Arg Xaa Arg Arg Arg Arg Xaa Gly 88 1 5 10 <210> 89 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 89 Arg Phe Phe Arg Phe Phe Arg Phe Phe Xaa 1 5 10 <210> 90 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Thr Arg Thr Arg Phe Leu Arg Arg Thr Xaa 90 1 5 10 <210> 91 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Phe Phe Arg Phe Phe Arg Phe Phe Arg Xaa 91 1 5 10 <210> 92 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> 92 Lys Thr Arg Thr Lys Phe Leu Lys Lys Thr Xaa 1 5 10 <210> 93 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 93 Lys Phe Phe Lys Phe Phe Lys Phe Phe Xaa 1 5 10 <210> 94 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Lys Phe Phe Lys Phe Phe Lys Phe Phe Lys Xaa 94 1 5 10 <210> 95 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 95 Arg Phe Phe Arg Phe Phe Xaa 1 5 <210> 96 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 96 Arg Phe Phe Arg Phe Phe Arg Xaa 1 5 <210> 97 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(3) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 97 Arg Xaa Xaa Arg Xaa Xaa Arg Xaa 1 5 <210> 98 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 98 1 5 10 <210> 99 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> 99 Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 100 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> 100 Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 101 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 101 Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 102 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 102 Arg Gin lie Lys lie Trp Phe Gin Asn Arg Arg Met Lys Trp Lys Lys 1 5 10 15 Gly Gly Xaa <210> 103 <211> 28 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (28)...(28) <223> Xaa = glycine or proline <400> 103 Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Lys lie Asn Leu 1 5 10 15 Lys Ala Leu Ala Ala Leu Ala Lys Lys lie Leu Xaa 20 25 <210> 104 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> Tyr Ala Arg Val Arg Arg Arg Gly Pro Arg Gly Tyr Ala Arg Val Arg 104 1 5 10 15 Arg Arg Gly Pro Arg Arg Xaa 20 <210> 105 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = glycine or proline <400> 105 Tyr Ala Arg Val Arg Arg Arg Gly Pro Arg Arg Xaa 1 5 10 <210> 106 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 106 Ala Lys Ala Ala Arg Gin Ala Ala Arg Xaa 1 5 10 <210> 107 <211> 35 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (35)...(35) <223> Xaa = glycine or proline <400> 107 Asp Ala Ala Thr Ala Thr Arg Gly Arg Ser Ala Ala Ser Arg Pro Thr 1 5 10 15 Glu Arg Pro Arg Ala Pro Ala Arg Ser Ala Ser Arg Pro Arg Arg Pro 20 25 30 Val Glu Xaa 35 <210> 108 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 108 Lys Glu Thr Trp Trp Glu Thr Trp Trp Thr Glu Trp Ser Gin Pro Lys 1 5 10 15 Lys Lys Arg Lys Val Xaa 20 <210> 109 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> Lys Glu Thr Trp Phe Glu Thr Trp Phe Thr Glu Trp Ser Gin Pro Lys 109 1 5 10 15 Lys Lys Arg Lys Val Xaa 20 <210> 110 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (17)...(17) <223> Xaa = glycine or proline <400> 110 Arg Gin lie Lys lie Trp Phe Gin Asn Arg Arg Met Lys Trp Lys Lys 1 5 10 15 Xaa <210> 111 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 111 Arg Arg Arg Arg Arg Arg Arg Gin lie Lys lie Trp Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp Lys Lys Gly Gly Xaa 20 25 <210> 112 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Arg Arg Gin Arg Arg Lys Lys Arg Cys Xaa 112 1 5 10 <210> 113 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 113 Cys Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 114 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Cys Xaa 114 1 5 10 <210> 115 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 115 Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Cys Phe Phe Xaa 1 5 10 <210> 116 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 116 Arg Arg Arg Arg Arg Arg Arg Arg Arg Cys Phe Phe Arg Xaa 1 5 10 <210> 117 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 117 Arg Arg Arg Arg Arg Arg Cys Phe Phe Arg Arg Arg Arg Xaa 1 5 10 <210> 118 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 118 Arg Arg Arg Arg Arg Phe Cys Phe Arg Arg Arg Arg Arg Xaa 1 5 10 <210> 119 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Arg Phe Phe Arg Arg Arg Arg Arg Xaa 119 1 5 10 <210> 120 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 120 Arg Arg Arg Arg Cys Phe Phe Arg Arg Arg Arg Arg Arg Xaa 1 5 10 <210> 121 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 121 Arg Arg Cys Phe Phe Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 10 <210> 122 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 122 Cys Phe Phe Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 10 <210> 123 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Cys Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Xaa 123 1 5 10 <210> 124 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Phe Phe Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Xaa 124 1 5 10 <210> 125 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 125 Arg Arg Arg Arg Arg Phe Phe Cys Phe Phe Arg Arg Arg Arg Arg Xaa 1 5 10 15 <210> 126 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> 126 Arg Arg Arg Arg Arg Arg Arg Arg Arg lie lie Xaa 1 5 10 <210> 127 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Phe Xaa 127 1 5 10 <210> 128 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Phe Phe Phe Xaa 128 1 5 10 <210> 129 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Xaa 129 1 5 10 <210> 130 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 130 Arg Arg Arg Arg Arg Arg Arg Phe Phe Xaa 1 5 <210> 131 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 131 Arg Arg Arg Arg Arg Phe Phe Xaa 1 5 <210> 132 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (3)...(3) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> 132 Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa 1 5 10 <210> 133 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2) ... (2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 133 1 5 10 <21Q> 134 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (1) ... (1) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa 134 1 5 10 <210> 135 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 135 1 5 10 <210> 136 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 136 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 137 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 137 Arg Xaa Arg Arg Xaa Arg Arg Xaa 1 5 <210> 138 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7) ... (7) <223> Xaa = glycine or proline <400> 138 Arg Xaa Arg Arg Xaa Arg Xaa 1 5 <210> 139 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (3)...(3) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Lys Xaa Arg Lys Xaa Arg Lys Xaa Arg Lys Xaa 139 1 5 10 <210> 140 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (3)...(3) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = glycine or proline <400> 140 Arg His Xaa Arg His Xaa Arg His Xaa Arg His Xaa 1 5 10 <210> 141 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 141 Arg Arg Arg Arg Arg Arg Arg Arg Arg Cys Phe Phe Arg Xaa 1 5 10 <210> 142 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (3)...(3) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa 142 1 5 10 <210> 143 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 143 1 5 10 <210> 144 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1, 4, 7, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa 144 1 5 10 <210> 145 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 145 1 5 10 <210> 146 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 146 1 5 10 <210> 147 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 147 1 5 10 15 <210> 148 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 11 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 148 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 149 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 149 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 150 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 150 1 5 10 15 <210> 151 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 10, 12, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 151 1 5 10 15 <210> 152 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 3, 5, 7, 11, 13, 15 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (17)...(17) <223> Xaa = glycine or proline <400> Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg 152 1 5 10 15 Xaa <210> 153 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 4, 8, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 2, 6, 10, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 153 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 154 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 10, 12, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 2, 4, 6, 8 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 154 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 155 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 6, 10, 12, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 155 1 5 10 15 <210> 156 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8, 10, 12, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 156 1 5 10 15 <210> 157 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 157 Arg Arg Arg Arg Xaa 1 5 <210> 158 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 158 Arg Arg Arg Arg Arg Xaa 1 5 <210> 159 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (7) ... (7) <223> Xaa = glycine or proline <400> 159 Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 160 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 160 Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 161 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 161 Arg Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 162 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Gly Arg Arg Arg Arg Xaa 162 1 5 10 <210> 163 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Arg Arg Arg Arg Phe Phe Arg Arg Arg Arg Arg Xaa 163 1 5 10 <210> 164 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 164 Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 165 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 165 Arg Arg Arg Gin Arg Arg Lys Lys Arg Xaa 1 5 10 <210> 166 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 166 Arg Xaa Arg Arg Xaa Arg Xaa 1 5 <210> 167 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 167 Arg Xaa Arg Arg Xaa Arg Xaa 1 5 <210> 168 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7) ... (7) <223> Xaa = glycine or proline <400> 168 Arg Xaa Arg Arg Xaa Arg Xaa 1 5 <210> 169 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7) ... (7) <223> Xaa = glycine or proline <400> 169 Arg Xaa Arg Arg Xaa Arg Xaa 1 5 <210> 170 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (8)...(8) <223> Xaa - glycine or proline <400> 170 Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 <210> 171 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 171 Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 <210> 172 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 172 Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 <210> 173 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2) ... (2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4) ... (4) <223> Xaa = C(0)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 173 Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 <210> 174 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = glycine or proline <400> Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 174 1 5 10 <210> 175 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = glycine or proline <400> 175 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 <210> 176 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2) ... (2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 176 1 5 10 <210> 177 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <22Q> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 177 1 5 10 <210> 178 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 178 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 179 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 179 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 180 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 180 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 181 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 8 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 181 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 182 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 182 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 183 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 183 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 184 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2) ... (2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 184 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 185 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 185 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 186 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <220> <221> MOD_RES <222> (4) ... (4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence. hydrogen or methyl <400> Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 186 1 5 10 <210> 187 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 187 1 5 10 <210> 188 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 188 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 189 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 189 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 190 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 190 1 5 10 <210> 191 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 191 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 192 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 192 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 193 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 193 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 194 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 194 1 5 10 <210> 195 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 195 1 5 10 <210> 196 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 196 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 197 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 197 Arg Xaa Arg Arg Asx Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 198 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 198 1 5 10 <210> 199 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 18 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 199 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 200 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or alanine <400> 200 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 201 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 201 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 202 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 202 1 5 10 <210> 203 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 203 1 5 10 <210> 204 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 204 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 205 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 2, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 205 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 206 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> 206 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 <210> 207 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 207 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 208 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4). . . (4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 208 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 209 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 209 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 210 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> 6, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 210 1 5 10 <210> 211 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 211 1 5 10 <210> 212 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 10, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 212 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 213 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 213 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 214 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> 6, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 214 1 5 10 <210> 215 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 10, 18 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> 215 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 216 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 6, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 216 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 217 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 10, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (120)...(120) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (160) ... (160) <223> Xaa = glycine or proline <400> 217 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 218 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4). . . (4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> 218 Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 219 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7) ... (7) <223> Xaa = -C(0)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> M0D_RES <222> (9)...(9) <223> Xaa = beta-alanine <220> <221> M0D_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> 219 Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 <210> 220 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = 6-aininohexanoic acid <220> <221> MOD_RES <222> (13)... (13) <223> Xaa = beta-alanine <220> <221> M0D_RES <222> (15)...(15) <223> Xaa = glycine or alanine <400> 220 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 221 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 221 Arg Xaa Arg Arg Xaa Arg Leu Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 222 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 222 1 5 10 <210> 223 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (18)...(18) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 223 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 224 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4). . . (4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (14) ... (4) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 224 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 225 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 225 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 226 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4). . . (4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> 226 Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 227 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 9 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 227 1 5 10 <210> 228 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa glycine or proline <400> 228 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 229 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 13 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 229 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 230 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 230 1 5 10 <210> 231 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 18 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 231 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 232 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = 6-aminihexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 232 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 233 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 233 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 234 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> 6, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 234 1 5 10 <210> 235 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 5, 9 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 235 1 5 10 <210> 236 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 10, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 236 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 237 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 5, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 237 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 238 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 6, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 238 1 5 10 <210> 239 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 10, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> 239 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 240 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 6, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 240 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 241 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 10, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 241 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 242 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11) ... (11) <223> Xaa = glycine or proline <400> 242 Arg Xaa Arg Xaa Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 243 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Xaa Arg Xaa Arg Xaa 243 1 5 10 <210> 244 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 244 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 15 <210> 245 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> 245 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 246 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 4, 8 <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 246 1 5 10 <210> 247 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (18)...(18) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 247 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Xaa Arg Xaa 20 <210> 248 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 248 Arg Xaa Arg Xaa Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa 1 5 10 15 <210> 249 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 10 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (12) ... (12) <223> Xaa = -C(O)-(CHRe)n-NH-wherein n is 2 to 7 and each Re is independently, at each occurrence, hydrogen or methyl <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> 249 Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 10 15 <210> 250 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 250 1 5 10 <210> 251 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 18 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 251 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa 20 <210> 252 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 11 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 252 1 5 10 <210> 253 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 253 Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Pro Xaa 1 5 10 <210> 254 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 13, 22 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 254 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Xaa Ala Ser 1 5 10 15 Ser Leu Asn lie Ala Xaa Cys Xaa 20 <210> 255 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20, 30 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 18, 22 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (32)...(32) <223> Xaa = glycine or proline <400> 255 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa Ala Ser Ser Leu Asn lie Ala Xaa Cys Xaa 20 25 30 <210> 256 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 20, 24 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> 2, 8, 18, 22 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 256 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Ala Ser Ser Leu Asn lie Ala 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Cys Xaa 20 25 <210> 257 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> 5, 11, 14 <223> Xaa = beta-alanine <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 257 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Xaa Ala Ser 1 5 10 15 Ser Leu Asn lie Ala Xaa 20 <210> 258 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 258 Thr His Arg Pro Pro Met Trp Ser Pro Val Trp Pro Xaa 1 5 10 <210> 259 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (12)...(12) <223> Xaa = glycine or proline <400> 259 His Arg Pro Pro Met Trp Ser Pro Val Trp Pro Xaa 1 5 10 <210> 260 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> 260 Thr His Arg Pro Pro Met Trp Ser Pro Val Xaa 1 5 10 <210> 261 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 261 Thr His Arg Pro Pro Met Trp Ser Pro Xaa 1 5 10 <210> 262 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 262 Thr His Arg Pro Pro Met Trp Ser Pro Val Phe Pro Xaa 1 5 10 <210> 263 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 263 Thr His Arg Pro Pro Met Trp Ser Pro Val Tyr Pro Xaa 1 5 10 <210> 264 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 264 Thr His Arg Pro Pro Met Trp Ser Pro Ala Trp Pro Xaa 1 5 10 <210> 265 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 265 Thr His Arg Pro Pro Met Trp Ser Pro Leu Trp Pro Xaa 1 5 10 <210> 266 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 266 Thr His Arg Pro Pro Met Trp Ser Pro lie Trp Pro Xaa 1 5 10 <210> 267 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> 267 Thr His Arg Pro Pro Met Trp Thr Pro Val Val Trp Pro Xaa 1 5 10 <210> 268 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 268 Thr His Arg Pro Pro Met Phe Ser Pro Val Trp Pro Xaa 1 5 10 <210> 269 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 269 Thr His Arg Pro Met Trp Ser Xaa 1 5 <210> 270 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> 270 His Arg Pro Pro Met Trp Ser Pro Val Trp Xaa 1 5 10 <210> 271 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 271 Thr His Arg Pro Pro Met Tyr Ser Pro Val Trp Pro Xaa 1 5 10 <210> 272 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <220> <221> MOD_RES <222> (6). . . (6) <223> Xaa = norleucine <400> 272 Thr His Arg Pro Pro Xaa Trp Ser Pro Val Trp Pro Xaa 1 5 10 <210> 273 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 273 Thr His Lys Pro Pro Met Trp Ser Pro Val Trp Pro Xaa 1 5 10 <210> 274 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> 274 Ser His Arg Pro Pro Met Trp Ser Pro Val Trp Pro Xaa 1 5 10 <210> 275 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 275 Ser Thr Phe Thr His Pro Arg Xaa 1 5 <210> 276 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 276 Tyr Asp lie Asp Asn Arg Arg Xaa 1 5 <210> 277 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 277 Ala Tyr Lys Pro Val Gly Arg Xaa 1 5 <210> 278 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 278 His Ala lie Tyr Pro Arg His Xaa 1 5 <210> 279 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 279 His Thr Pro Asn Ser Thr His Xaa 1 5 <210> 280 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 280 Ala Ser Ser Pro Val His Arg Xaa 1 5 <210> 281 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 281 Ser Ser Leu Pro Leu Arg Lys Xaa 1 5 <210> 282 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 282 Lys Lys Arg Ser Xaa 1 5 <210> 283 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 283 Lys Arg Ser Lys Xaa 1 5 <210> 284 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 284 Lys Lys Arg Ser Lys Xaa 1 5 <210> 285 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 285 Lys Ser Arg Lys Xaa 1 5 <210> 286 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 286 Ser Arg Lys Arg Xaa 1 5 <210> 287 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 287 Arg Lys Arg Lys Xaa 1 5 <210> 288 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 288 Lys Ser Arg Lys Arg Xaa 1 5 <210> 289 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 289 Gin His Pro Pro Trp Arg Val Xaa 1 5 <210> 290 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 290 Thr His Pro Pro Thr Thr His Xaa 1 5 <210> 291 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 291 Tyr Lys His Thr Pro Thr Thr Xaa 1 5 <210> 292 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 292 Gin Gly Met His Arg Gly Thr Xaa 1 5 <210> 293 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 293 Ser Arg Lys Arg Lys Xaa 1 5 <210> 294 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 294 Lys Ser Arg Lys Arg Lys Xaa 1 5 <210> 295 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 295 Pro Lys Lys Lys Arg Lys Val Xaa 1 5 <210> 296 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 296 Gly Lys Lys Arg Ser Lys Val Xaa 1 5 <210> 297 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 297 Lys Ser Arg Lys Arg Lys Leu Xaa 1 5 <210> 298 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 298 His Ser Pro Ser Lys lie Pro Xaa 1 5 <210> 299 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 299 His Met Ala Thr Phe His Tyr Xaa 1 5 <210> 300 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 300 Ala Gin Pro Asn Lys Phe Lys Xaa 1 5 <210> 301 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 301 Asn Leu Thr Arg Leu His Thr Xaa 1 5 <210> 302 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 302 Lys Lys Lys Arg Xaa 1 5 <210> 303 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = glycine or proline <400> 303 Lys Lys Arg Lys Xaa 1 5 <210> 304 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 304 Lys Lys Lys Arg Lys Xaa 1 5 <210> 305 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 305 Arg Arg Arg Arg Arg Arg Gin lie Lys lie Trp Phe Gin Asn Arg Arg 1 5 10 15 Met Lys Trp Lys Lys Gly Gly Cys Xaa 20 25 <210> 306 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 306 Arg Arg Arg Arg Arg Arg Arg Gin lie Lys lie Trp Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp Lys Lys Gly Gly Cys Xaa 20 25 <210> 307 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> 307 Arg Gin lie Lys lie Trp Phe Gin Asn Arg Arg Met Lys Trp Lys Lys 1 5 10 15 Gly Gly Cys Xaa 20 <210> 308 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 308 Arg Arg Arg Arg Arg Arg Arg Gin lie Lys lie Trp Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp Lys Lys Cys Xaa 20 <210> 309 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (29)...(29) <223> Xaa = glycine or proline <400> 309 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Gin lie Lys lie Trp Phe 1 5 10 15 Gin Asn Arg Arg Met Lys Trp Lys Lys Gly Gly Cys Xaa 20 25 <210> 310 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 17, 19, 21, 23 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 310 Arg Arg Arg Arg Arg Arg Arg Gin lie Lys lie Leu Phe Gin Asn Arg 1 5 10 15 Xaa Arg Xaa Arg Xaa Arg Xaa Cys Xaa 20 25 <210> 311 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Cys Xaa 311 1 5 10 <210> 312 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Cys Xaa 312 1 5 10 15 <210> 313 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27) ... (27) <223> Xaa = glycine or proline <400> 313 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Gly Gly Cys Xaa 20 25 <210> 314 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 314 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 315 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 315 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Met Lys Trp Lys Lys Cys Xaa 20 <210> 316 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 316 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 317 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 317 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 His Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 318 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 318 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 319 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 319 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 320 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 320 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Ala Cys Xaa 20 25 <210> 321 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 321 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 322 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 322 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Arg Cys Xaa 20 25 <210> 323 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 323 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 324 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 324 Arg Ala Arg Ala Arg Ala Arg Ala Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 325 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 325 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 326 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 326 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 327 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 327 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 328 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 328 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 329 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 329 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Leu Tyr Ser Pro Leu Ser Phe 1 5 10 15 Gin Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 330 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 330 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Ser lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 331 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 331 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 332 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 332 Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr Xaa Arg Met 1 5 10 15 Lys Trp His Lys Ala Cys Xaa 20 <210> 333 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 333 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie His lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 334 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 334 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie His lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 335 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 335 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 336 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 336 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 337 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (260)...(260) <223> Xaa = glycine or proline <400> 337 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 338 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 338 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 339 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 339 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 340 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aininohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 340 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 341 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 341 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 342 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 342 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 343 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 343 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 344 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 344 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 345 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 345 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 346 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 346 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie lie Leu Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 347 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 347 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie lie Leu Phe Gin Asn Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 348 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 348 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Lys lie Leu Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 349 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 349 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Lys lie Leu Phe Gin Asn Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 350 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 350 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa lie Leu Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 351 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 10, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 351 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa lie Leu Phe Gin Asn Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 352 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 352 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg His lie Leu Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 353 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 353 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg His lie Leu Phe Gin Asn Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 354 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 354 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg lie Leu Phe Gin Asn Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 355 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 355 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg lie Leu Phe Gin Asn Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 356 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 356 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Asn Arg Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 357 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 357 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Asn Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 358 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 358 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Tyr 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 359 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 359 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 360 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 360 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 361 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 361 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 362 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 362 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Tyr 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 363 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 363 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 364 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 364 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Tyr 1 5 10 15 Arg Arg Met Lys Trp His Lys Xaa 20 <210> 365 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 365 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Xaa 20 <210> 366 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa - glycine or proline <400> 366 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie lie Leu Phe Gin Tyr Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 367 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 367 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie lie Leu Phe Gin Tyr Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 368 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 368 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Lys lie Leu Phe Gin Tyr Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 369 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 369 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Lys lie Leu Phe Gin Tyr Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 370 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 10 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 370 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa lie Leu Phe Gin Tyr Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 371 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8,10, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 371 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa lie Leu Phe Gin Tyr Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 372 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 372 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg His lie Leu Phe Gin Tyr Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 373 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 373 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg His lie Leu Phe Gin Tyr Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 374 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 374 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg lie Leu Phe Gin Tyr Arg 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 375 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 375 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg lie Leu Phe Gin Tyr Xaa 1 5 10 15 Arg Met Lys Trp His Lys Xaa 20 <210> 376 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 376 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 377 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 377 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 378 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 378 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 1 5 10 <210> 379 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa 379 1 5 10 <210> 380 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 380 Arg Ala Arg Arg Ala Arg Xaa 1 5 <210> 381 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 381 Arg Ala Arg Arg Ala Arg Arg Ala Arg Xaa 1 5 10 <210> 382 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (13)...(13) <223> Xaa = glycine or proline <400> Arg Ala Arg Arg Ala Arg Arg Ala Arg Arg Arg Ala Arg Xaa 382 1 5 10 <210> 383 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 383 Arg Xaa Arg Arg Xaa Arg lie Xaa Xaa 1 5 <210> 384 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 384 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg Xaa 1 5 10 <210> 385 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (5)...(5) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 385 Arg Ala Arg Arg Xaa Arg Arg Ala Arg Xaa 1 5 10 <210> 386 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 386 Arg Arg Arg Arg Arg Xaa 1 5 <210> 387 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (7)...(7) <223> Xaa = glycine or proline <400> 387 Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 388 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 388 Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 389 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Cys Xaa 389 1 5 10 <210> 390 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Xaa Cys Xaa 390 1 5 10 15 <210> 391 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 391 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Gly Gly Cys Xaa 20 25 <210> 392 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 392 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 393 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 393 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Met Lys Trp Lys Lys Cys Xaa 20 <210> 394 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 394 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 395 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 395 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 His Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 396 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 396 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 397 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 397 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 398 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 398 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp Lys Ala Cys Xaa 20 25 <210> 399 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 399 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 400 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 400 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Arg Cys Xaa 20 25 <210> 401 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6, 8 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 401 Arg Xaa Arg Xaa Arg Xaa Arg Xaa Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 402 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 402 Arg Ala Arg Ala Arg Ala Arg Ala Arg lie Lys lie Leu Phe Gin Asn 1 5 10 15 Arg Arg Met Lys Trp Lys Lys Cys Xaa 20 25 <210> 403 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 403 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 404 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 404 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 405 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 405 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Arg lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 406 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 406 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 407 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 407 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Leu Tyr Ser Pro Leu Ser Phe 1 5 10 15 Gin Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 408 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 408 Arg Arg Met Lys Trp His Lys Xaa 1 5 <210> 409 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (1)...(1) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 409 Xaa Arg Met Lys Trp His Lys Xaa 1 5 <210> 410 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 410 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa Arg Met Lys Trp His Lys Xaa 20 25 <210> 411 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 411 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa Arg Met Lys Trp His Lys Xaa 20 25 <210> 412 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 412 Arg Arg Arg Arg Arg Arg Arg Gin lie Lys lie Leu Phe Gin Asn Pro 1 5 10 15 Lys Lys Lys Arg Lys Val Gly Gly Cys Xaa 20 25 <210> 413 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (17)...(17) <223> Xaa = glycine or proline <400> 413 His His Phe Phe Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Cys 1 5 10 15 Xaa <210> 414 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 414 His His His His His His Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe 1 5 10 15 Phe Cys Xaa <210> 415 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (21) ... (21) <223> Xaa = glycine or proline <400> 415 His His His His His His Phe Phe Arg Arg Arg Arg Arg Arg Arg Arg Arg 1 5 10 15 Arg Phe Phe Cys Xaa 20 <210> 416 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <220> <221> MOD_RES <222> 6, 7 <223> Xaa = 6-aminohexanoic acid <400> 416 His His His His His Xaa Xaa Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg 1 5 10 15 Phe Phe Cys Xaa 20 <210> 417 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <220> <221> MOD_RES <222> 7, 8 <223> Xaa = 6-aminohexanoic acid <400> His His His His His His Xaa Xaa Phe Phe Arg Arg Arg Arg Arg Arg 417 1 5 10 15 Arg Arg Arg Phe Phe Cys Xaa 20 <210> 418 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 4, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21) ... (21) <223> Xaa = glycine or proline <400> 418 His His His Xaa Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Phe Phe Xaa 1 5 10 15 His His His Cys Xaa 20 <210> 419 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (1) ... (1) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 419 Xaa Arg Met Lys Trp His Lys Xaa 1 5 <210> 420 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (1)...(1) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 420 Xaa Arg Trp Lys Trp His Lys Xaa 1 5 <210> 421 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 421 Arg Xaa Arg Ala Arg Xaa Arg Xaa 1 5 <210> 422 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 4, 6 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 422 Arg Xaa Arg Xaa Arg Xaa Arg Xaa 1 5 <210> 423 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (4)...(4) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (8) ... (8) <223> Xaa = glycine or proline <400> 423 Arg Ala Arg Xaa Arg Ala Arg Xaa 1 5 <210> 424 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (2)...(2) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (6)...(6) <223> Xaa = glycine or proline <400> 424 Arg Xaa Arg Ala Arg Xaa 1 5 <210> 425 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 425 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa His Met Lys Trp His Lys Xaa 20 25 <210> 426 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 426 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa Arg Trp Lys Trp His Lys Xaa 20 25 <210> 427 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 427 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa His Trp Lys Trp His Lys Xaa 20 25 <210> 428 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 428 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 429 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 23, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 429 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 20 25 <210> 430 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 24 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 430 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Arg Xaa Arg Xaa 20 25 <210> 431 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 23 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 431 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Ala Arg Xaa Arg Ala Arg Xaa 20 25 <210> 432 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 432 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 433 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 433 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa 20 25 <210> 434 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 434 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa Arg Met Lys Trp His Lys Xaa 20 25 <210> 435 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 435 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa His Met Lys Trp His Lys Xaa 20 25 <210> 436 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 436 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa Arg Trp Lys Trp His Lys Xaa 20 25 <210> 437 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 437 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa His Trp Lys Trp His Lys Xaa 20 25 <210> 438 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 438 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 439 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 23, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 439 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 20 25 <210> 440 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 24 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 440 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Arg Xaa Arg Xaa 20 25 <210> 441 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 23 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 441 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Ala Arg Xaa Arg Ala Arg Xaa 20 25 <210> 442 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 442 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 443 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 443 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa 20 25 <210> 444 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 444 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa His Met Lys Trp His Lys Xaa 20 25 <210> 445 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19-20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 445 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa Arg Trp Lys Trp His Lys Xaa 20 25 <210> 446 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 446 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Xaa His Trp Lys Trp His Lys Xaa 20 25 <210> 447 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 447 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 448 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 23, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27) ... (27) <223> Xaa = glycine or proline <400> 448 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 20 25 <210> 449 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 24 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 449 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Arg Xaa Arg Xaa 20 25 <210> 450 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 23 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27) ... (27) <223> Xaa = glycine or proline <400> 450 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Ala Arg Xaa Arg Ala Arg Xaa 20 25 <210> 451 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 451 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 452 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 452 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 Phe Gin Xaa Arg Xaa Arg Ala Arg Xaa 20 25 <210> 453 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 453 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa Arg Met Lys Trp His Lys Xaa 20 25 <210> 454 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 454 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa His Met Lys Trp His Lys Xaa 20 25 <210> 455 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 455 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa Arg Trp Lys Trp His Lys Xaa 20 25 <210> 456 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, <223> Xaa = 6-aminohexanoic acid 19-20 <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 456 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Xaa His Trp Lys Trp His Lys Xaa 20 25 <210> 457 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 457 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 458 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 23, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 458 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Xaa Arg Xaa Arg Xaa 20 25 <210> 459 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 24 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 459 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Arg Xaa Arg Xaa 20 25 <210> 460 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 23 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 460 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Ala Arg Xaa Arg Ala Arg Xaa 20 25 <210> 461 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21, 25 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27) ... (27) <223> Xaa = glycine or proline <400> 461 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa Arg Xaa 20 25 <210> 462 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 1-14, 19, 21 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (25)...(25) <223> Xaa = glycine or proline <400> 462 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa lie Leu 1 5 10 15 lie Gin Xaa Arg Xaa Arg Ala Arg Xaa 20 25 <210> 463 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (15)...(15) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Ala Arg Arg Xaa Arg Arg Ala Arg Xaa Ala Xaa 463 1 5 10 15 <210> 464 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 464 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 465 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 465 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 466 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 466 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Ala Cys Xaa 20 <210> 467 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (14)...(14) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Cys Xaa 467 1 5 10 <210> 468 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 468 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 469 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 469 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 470 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 11, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 470 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 471 <211> 27 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (27)...(27) <223> Xaa = glycine or proline <400> 471 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg Leu Tyr Ser Pro Leu Ser Phe 1 5 10 15 Gin Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 472 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 472 Arg Xaa Arg Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 473 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 8, 14 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 473 Arg Xaa Arg Arg Xaa Arg lie Xaa lie Leu Phe Gin Tyr Xaa Arg Met 1 5 10 15 Lys Trp His Lys Ala Cys Xaa 20 <210> 474 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 474 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 475 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 475 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 476 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 476 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 477 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 477 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 478 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 478 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 479 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 479 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 480 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 480 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Ala Cys Xaa 20 <210> 481 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 481 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa His 1 5 10 15 Trp Lys Trp His Lys Ala Cys Xaa 20 <210> 482 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 482 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Ala Cys Xaa 20 <210> 483 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 483 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Ala Cys Xaa 20 <210> 484 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 484 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 485 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 485 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa 1 5 10 15 Arg Cys Xaa <210> 486 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 486 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Ala Cys Xaa 20 <210> 487 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 487 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Ala Cys Xaa 20 <210> 488 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24) ... (24) <223> Xaa = glycine or proline <400> 488 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Ala Cys Xaa 20 <210> 489 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21) ... (21) <223> Xaa = glycine or proline <400> 489 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa 1 5 10 15 Arg Cys Tyr Ser Xaa 20 <210> 490 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 490 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Ala 1 5 10 15 Arg Xaa Arg Ala Arg Ala Cys Xaa 20 <210> 491 <211> 24 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (24)...(24) <223> Xaa = glycine or proline <400> 491 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Ala Cys Xaa 20 <210> 492 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 492 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Ala Cys Xaa 20 <210> 493 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 493 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Ala Cys Xaa 20 <210> 494 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 494 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Ala Cys Xaa 20 <210> 495 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (23)...(23) <223> Xaa = glycine or proline <400> 495 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Ala Cys Xaa 20 <210> 496 <211> 26 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (26)...(26) <223> Xaa = glycine or proline <400> 496 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie His lie Leu Phe Gin Asn 1 5 10 15 Xaa Arg Met Lys Trp His Lys Ala Cys Xaa 20 25 <210> 497 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (16)...(16) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Ala Arg Arg Xaa Arg Arg Ala Arg Xaa Ala Cys Xaa 497 1 5 10 15 <210> 498 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 498 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 499 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 499 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 500 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 500 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Xaa 20 <210> 501 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 501 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 502 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 502 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Xaa 20 <210> 503 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 503 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa 20 <210> 504 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21) ... (21) <223> Xaa = glycine or proline <400> 504 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Xaa 20 <210> 505 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 505 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Ala 1 5 10 15 Arg Xaa Arg Ala Arg Xaa 20 <210> 506 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa 506 1 5 10 15 Arg Ala Arg Xaa 20 <210> 507 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 507 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 508 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 508 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 509 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 509 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Xaa 20 <210> 510 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 510 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 511 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 511 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Xaa 20 <210> 512 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 512 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa 20 <210> 513 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21)...(21) <223> Xaa = glycine or proline <400> 513 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Xaa 20 <210> 514 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 514 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Ala 1 5 10 15 Arg Xaa Arg Ala Arg Xaa 20 <210> 515 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 8, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20)...(20) <223> Xaa = glycine or proline <400> 515 Arg Xaa Arg Arg Ala Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa 20 <210> 516 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 516 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 517 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 517 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 518 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 518 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Xaa 20 <210> 519 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Xaa Arg 519 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 520 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 520 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Xaa 20 <210> 521 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 521 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa 20 <210> 522 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21)...(21) <223> Xaa = glycine or proline <400> 522 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Xaa 20 <210> 523 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 523 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Ala 1 5 10 15 Arg Xaa Arg Ala Arg Xaa 20 <210> 524 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 524 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu Phe Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa 20 <210> 525 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 525 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Xaa His 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 526 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 526 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 527 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 527 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Trp Lys Trp His Lys Xaa 20 <210> 528 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22)...(22) <223> Xaa = glycine or proline <400> 528 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Xaa Arg 1 5 10 15 Met Lys Trp His Lys Xaa 20 <210> 529 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 529 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa Arg Xaa 20 <210> 530 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 18, 20 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 530 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Xaa Arg Xaa Arg Xaa 20 <210> 531 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16, 19 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (21)...(21) <223> Xaa = glycine or proline <400> 531 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Arg Xaa Arg Xaa 20 <210> 532 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 18 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (22) ... (22) <223> Xaa = glycine or proline <400> 532 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Arg Ala 1 5 10 15 Arg Xaa Arg Ala Arg Xaa 20 <210> 533 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 5, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (20) ... (20) <223> Xaa = glycine or proline <400> 533 Arg Ala Arg Arg Xaa Arg Arg Ala Arg lie Leu lie Gin Tyr Arg Xaa 1 5 10 15 Arg Ala Arg Xaa 20 <210> 534 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = glycine or proline <400> 534 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa His Met Lys Trp 1 5 10 15 His Lys Xaa <210> 535 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 535 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg Met Lys Trp 1 5 10 15 His Lys Xaa <210> 536 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 536 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg Trp Lys Trp 1 5 10 15 His Lys Xaa <210> 537 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 537 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Xaa Arg Met Lys Trp 1 5 10 15 His Lys Xaa <210> 538 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 538 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Ala Arg 1 5 10 15 Xaa Arg Xaa <210> 539 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 15, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 539 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Xaa Arg 1 5 10 15 Xaa Arg Xaa <210> 540 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (18)...(18) <223> Xaa = glycine or proline <400> Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Arg Xaa 540 1 5 10 15 Arg Xaa <210> 541 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 541 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Ala Arg Xaa Arg 1 5 10 15 Ala Arg Xaa <210> 542 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (17)...(17) <223> Xaa = glycine or proline <400> 542 Arg Xaa Arg Arg Xaa Arg lie Leu Phe Gin Tyr Arg Xaa Arg Ala Arg 1 5 10 15 Xaa <210> 543 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 543 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa His Met Lys Trp 1 5 10 15 His Lys Xaa <210> 544 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 544 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg Met Lys Trp 1 5 10 15 His Lys Xaa <210> 545 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aininohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 545 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg Trp Lys Trp 1 5 10 15 His Lys Xaa <210> 546 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 12 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 546 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Xaa Arg Met Lys Trp 1 5 10 15 His Lys Xaa <210> 547 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 547 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa Arg Ala Arg 1 5 10 15 Xaa Arg Xaa <210> 548 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 15, 17 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400> 548 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa Arg Xaa Arg 1 5 10 15 Xaa Arg Xaa <210> 549 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 13, 16 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (18)...(18) <223> Xaa = glycine or proline <400> 549 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa Arg Arg Xaa 1 5 10 15 Arg Xaa <210> 550 <211> 19 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> 2, 5, 15 <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (19)...(19) <223> Xaa = glycine or proline <400 550 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Ala Arg Xaa Arg 1 5 10 15 Ala Arg Xaa <210> 551 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> M0D_RES <222> 2, 5, 13 <223> Xaa = 6-aminohexanoic acid <220> <221> M0D_RES <222> (17) ... (17) <223> Xaa = glycine or proline <400> 551 Arg Xaa Arg Arg Xaa Arg lie Leu lie Gin Tyr Arg Xaa Arg Ala Arg 1 5 10 15 Xaa <210> 552 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> M0D_RES <222> (4)...(14) <223> Xaa = 6-aminohexanoic acid <220> <221> MOD_RES <222> (18)...(18) <223> Xaa - glycine or proline <400> Pro Arg Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Pro Arg 552 1 5 10 15 Gly Xaa <210> 553 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 553 Arg Arg Arg Arg Arg Arg Arg Arg Arg Xaa 1 5 <210> 554 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 554 Arg Arg Met Lys Trp Lys Lys Xaa 1 5 <210> 555 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 555 Pro Lys Lys Lys Arg Lys Val Xaa 1 5 <210> 556 <211> 33 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (33)...(33) <223> Xaa = glycine or proline <400> 556 Cys Lys Asp Glu Pro Gin Arg Arg Ser Ala Arg Leu Ser Ala Lys Pro 1 5 10 15 Ala Pro Pro Lys Pro Glu Pro Lys Pro Lys Lys Ala Pro Ala Lys Lys 20 25 30 Xaa <210> 557 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 557 Arg Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 558 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 558 Arg Lys Lys Arg Arg Gin Arg Arg Xaa 1 5 <210> 559 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (8)...(8) <223> Xaa = glycine or proline <400> 559 Arg Lys Lys Arg Arg Gin Arg Xaa 1 5 <210> 560 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 560 Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 <210> 561 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (9)...(9) <223> Xaa = glycine or proline <400> 561 Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 <210> 562 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xa = glycine or proline <400> 562 Ala Lys Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 563 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 563 Arg Ala Lys Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 564 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 564 Arg Lys Ala Arg Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 565 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (10)...(10) <223> Xaa = glycine or proline <400> 565 Arg Lys Lys Ala Arg Gin Arg Arg Arg Xaa 1 5 10 <210> 566 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> cell penetrating peptide <220> <221> MOD_RES <222> (11)...(11) <223> Xaa = glycine or proline <400> Cys Arg Trp Arg Trp Lys Cys Cys Lys Lys Xaa 566 1 5 10 <210> 567 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 567 cggtccacgt agactaacaa ct 22 <210> 568 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 568 gaagttcaca cagataaact tct 23 <210> 569 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 569 tttcgacatc ggttagaaga ctcat 25 <210> 570 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 570 tttcgacatc ggttagaaga ctcat 25 <210> 571 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 571 gagacgccat gatgtggatg tc 22 <210> 572 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 572 gaaacacgga cacccaaagt agt 23 <210> 573 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 573 tcccagcgtc aatatgctgt tt 22 <210> 574 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 574 gcctaggatc cacggtgcgc 20 <210> 575 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> synthetic oligonucleotide <400> 575 gggacaaaat ggatcccatt attaatggaa attctgctaa 40

Claims (65)

(a) a carrier peptide comprising an amino acid subunit, the carrier peptide comprising a proline (P) amino acid subunit at the carboxy terminus of the carrier peptide;
(b) a nucleic acid analog comprising an uncharged backbone and a target nucleotide sequence for sequence-specific binding to a target nucleic acid and having a length of 8 to 40 bases; and
(c) a covalent attachment between said carrier peptide and said nucleic acid analog comprising said carboxy-terminal proline with an optional linker of up to 18 elements in length comprising an alkyl, alkoxy, or alkylamino group, or combinations thereof;
As a conjugate (conjugate) comprising a,
2 to 20 amino acid subunits are positively charged amino acids, up to 7 contiguous amino acid subunits are arginine, and the covalent attachment between the carrier peptide and the nucleic acid analog is 6-aminohexanoic acid or β-alanine not, the conjugate. The conjugate of claim 1 , wherein the nucleic acid analog is 8 to 20 bases in length. The conjugate of claim 1 , wherein the nucleic acid analog is 8 to 16 bases in length. The conjugate of claim 1 , wherein the nucleic acid analog is 10 to 30 bases in length. The conjugate of claim 1 , wherein the nucleic acid analog is 12 to 25 bases in length. The conjugate of claim 1 , wherein the nucleic acid analog is 8 to 12 bases in length. According to claim 1, wherein the carrier peptide is SEQ ID NOs: 60, 69, 70, 89-121, 125, 130-160, 162-257, 276, 277, 281-288, 293-297, 300, 302-412 , 419-552, and 554-566. The conjugate of claim 1 , wherein the carrier peptide is selected from SEQ ID NOs: 130, 157-160, 251, 256, 386-388, and 540. The conjugate of claim 1 , wherein the carrier peptide is SEQ ID NO:159. The conjugate of claim 1 , wherein the carrier peptide is a carrier peptide of the formula selected from:

;

;

; and

;
where Y is an integer from 4 to 7; R is selected from H, acetyl, benzoyl and stearoyl. 11. The conjugate of claim 10, wherein the carrier peptide is a carrier peptide of the formula:

wherein Y is 6 and R is selected from H, acetyl, benzoyl and stearoyl. The method of claim 1, wherein the conjugate is

,

or a pharmaceutically acceptable salt of any one of these,
wherein the carrier peptide is as defined in claim 1 ;
X is an integer from 0 to 38;
R is selected from H, acetyl, benzoyl and stearoyl;
R ¹ is selected from H, acetyl, benzoyl and stearoyl;
R ² is selected from H, acetyl, benzoyl, stearoyl, trityl and 4-methoxytrityl;
each Pi is a purine or pyrimidine base-pairing moiety, each Pi together forming the target base sequence,
Xaa is the carboxy-terminal proline. 13. The conjugate of claim 12, wherein X is 6 to 18. 13. The conjugate of claim 12, wherein X is 6 to 14. 13. The conjugate of claim 12, wherein X is 8 to 28. 13. The conjugate of claim 12, wherein X is 10-23. 13. The conjugate of claim 12, wherein X is 6 to 10. 13. The conjugate of claim 12, wherein the carrier peptide is selected from SEQ ID NOs: 130, 157-160, 251, 256, 386-388, and 540. 13. The conjugate of claim 12, wherein the carrier peptide is SEQ ID NO: 159. 13. The conjugate of claim 12, wherein each Pi is independently selected from adenine, cytosine, guanine, uracil, thymine and inosine.

;

;

;

;

;

;

; and

As a compound selected from, or a pharmaceutically acceptable salt thereof,
here,
X is an integer from 0 to 38;
Y is an integer from 4 to 9;
Z is 6 or 9;
R is selected from H, acetyl, benzoyl and stearoyl;
R ¹ is selected from H, acetyl, benzoyl and stearoyl;
R ² is selected from H, acetyl, benzoyl, stearoyl, trityl and 4-methoxytrityl;
wherein each Pi is a purine or pyrimidine base-pairing moiety, wherein each Pi together form the target base sequence. 22. The compound of claim 21, wherein X is 6 to 18. 22. The compound of claim 21, wherein X is 6 to 14. 22. The compound of claim 21, wherein X is 8 to 28. 22. The compound of claim 21, wherein X is 10-23. 22. The compound of claim 21, wherein X is 6 to 10. 22. The compound of claim 21, wherein each Pi is independently selected from adenine, cytosine, guanine, uracil, thymine and inosine. 22. The method of claim 21, wherein the compound is

or a pharmaceutically acceptable salt thereof. 29. The compound of claim 28, wherein R is H. 29. The compound of claim 28, wherein R is acetyl. 29. The compound of claim 28, wherein X is 6 to 18. 29. The compound of claim 28, wherein X is 6 to 14. 29. The compound of claim 28, wherein X is 8 to 28. 29. The compound of claim 28, wherein X is 10-23. 29. The compound of claim 28, wherein X is 6 to 10. 29. The compound of claim 28, wherein each Pi is independently selected from adenine, cytosine, guanine, uracil, thymine and inosine. The method of claim 1, wherein the conjugate is

,

, or a pharmaceutically acceptable salt of any one of these,
wherein the carrier peptide is as defined in claim 1 ;
Z is an integer from 0 to 38;
R is selected from H, acetyl, benzoyl and stearoyl;
R ¹ is selected from H, acetyl, benzoyl and stearoyl;
R ² is selected from H, acetyl, benzoyl, stearoyl, trityl and 4-methoxytrityl;
X is independently in each case

,

, and

is selected from, wherein R ³ is selected from H, methyl, and an electron pair;
each Pi is a purine or pyrimidine base-pairing moiety, each Pi together forming the target base sequence,
Xaa is the carboxy-terminal proline. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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