WO2005007675A2 - Acides amino triazole-$g(e) - Google Patents

Acides amino triazole-$g(e) Download PDF

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WO2005007675A2
WO2005007675A2 PCT/US2004/022081 US2004022081W WO2005007675A2 WO 2005007675 A2 WO2005007675 A2 WO 2005007675A2 US 2004022081 W US2004022081 W US 2004022081W WO 2005007675 A2 WO2005007675 A2 WO 2005007675A2
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amino acid
peptide
chirality
cyclic
peptides
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PCT/US2004/022081
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WO2005007675A3 (fr
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M. Reza Ghadiri
William S. Horne
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the invention relates to 1,2,3-triazole ⁇ -amino acids and peptides or polypeptides having at least one 1,2,3-triazole ⁇ -amino acid.
  • Background includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.
  • Peptides and polypeptides are increasingly used both in vitro and in vivo for diagnostic and therapeutic purposes. However, peptides and polypeptides made from natural amino acids are often prone to protease degradation and provide limited opportunities for attachment of functional groups and other useful moieties.
  • the peptidyl backbone formed from natural amino acids provides few useful attachment sites for addition of such functional groups and other useful moieties. While some modified amino acids can be used, synthesis of peptides from such modified amino acids can be expensive and is sometimes problematic. Hence, new types of amino acids are needed that can readily be synthesized, that can easily be incorporated into peptides and that provide convenient attachment sites for functional groups and other useful moieties. Summary The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this Summary. The inventions described and claimed herein are not limited to or by the features or embodiments identified in this Summary, which is included for purposes of illustration only and not restriction. The invention provides a 1,2,3-triazole ⁇ -amino acid of formula I:
  • R is any amino acid side chain; Ri is H, a protecting group or an amino acid; and R 2 is H, a protecting group or an amino acid.
  • the invention also provides a peptide having at least one 1,2,3-triazole ⁇ -amino acid of formula I.
  • the peptide can be a linear or cyclic peptide.
  • the invention also provides a composition comprising a carrier and a peptide comprising at least one 1,2,3-triazole ⁇ -amino acid of formula I.
  • the peptide can be a linear or cyclic peptide.
  • the invention provides cyclic peptides that can self-assemble into supramolecular structures such as nanotubes. The epsilon amino acid residues of these peptides provide linkage points for surface functionalization of the nanotubes.
  • the invention provides a cyclic peptide that has an amino acid sequence comprising formula II: R 1 -(X 1 ) p -(Y 1 ) q -(Z 1 ) r -(X 2 ) p -(Y 2 ) q -(Z 2 ) ...-(X n ) p -(Y n ) q -(Z n ) r -X-R 2 II wherein: each p, q, or r is separately an integer of 1 or 0; at least one p is 1; X is an epsilon amino acid residue of the following formula:
  • R 3 , Ri, and R 5 are separately any amino acid, functional group, protecting group; each Y is any ⁇ amino acid residue; each Z is any ⁇ amino acid residue; and Ri and R can separately be a hydrogen atom, hydroxy group, protecting group or Ri and R 2 can be linked to form a cyclic peptide when there are at least three residues in the peptide.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula III: cyclo[X ⁇ -Y ⁇ -X 2 -Y 2 ] III wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula IV: cyclofXi-ZrXz-Z;,] IV wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Z is a ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acids and where each Z has the same chirality as the all the other Z groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula V: cyclopCi- X 2 - X 3 ] V wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula VI: cyclo[X ⁇ - X 2 - X 3 - X 4 ] VI wherein each X is separately an ⁇ amino acid with alternating R,R or S,S substitution pattern throughout the peptide.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula VII: cyclo[X ⁇ -Y Y 2 -X 2 -Y 3 -Y 4 ] VII wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same' chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula VUI: cyclop -Yi -Y2-X2- Y3-Y4-X3-Y5-Y6] VIII wherein: each X is an ⁇ amino acid as described above with either an R,R or S.S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula IX: Rr(X ⁇ ) p -(Y ⁇ ) q -(Z ⁇ ) r -(X 2 ) p -(Y 2 ) q -(Z 2 ) r -...-(X n ) p -(Y n ) q -(Z n ) r -X-R 2 IX wherein: each p, q, or r is separately an integer of 1 or 0; at least one p is 1; X is an epsilon amino acid residue of the following formula:
  • R4 R 5 R 3 , R4, and R 5 are separately any amino acid, functional group, protecting group; each Y is any ⁇ amino acid residue; each Z is any ⁇ amino acid residue; and Ri and R 2 can separately be a hydrogen atom, hydroxy group, protecting group or R] and R 2 can be linked to form a cyclic peptide when there are at least two residues in the peptide.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula X: cyclo[X ⁇ -Y ⁇ -X 2 -Y2-X3-Y3] X wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • the cyclic peptides of the invention can self-assemble into a supramolecular structure.
  • Such cyclic peptides are useful for small molecule transport, and for treating a variety of conditions including microbial infections, fungal infections, viral infections, and cancer.
  • the invention also provides a composition having a carrier and any of the cyclic peptides of the invention is also provided herein.
  • the carrier can be a pharmaceutically effective carrier.
  • Crystal structure of 1 (a) single molecule viewed from the top (solvent omitted), (b) crystal packing viewed along the tube axis (solvent omitted), (c) one tube viewed from the side (solvent omitted), and (d) expanded view of the interaction between two rings with heteroatom-heteroatom distances for indicated hydrogen-bonding moieties labeled in A (protons omitted).
  • Figure 3. Structure of compound II, a compound of formula III (Fig. 3 A); and Compound III, a compound according to formula VI (Fig. 3B).
  • the present invention provides peptides and polypeptides having at least one 1,2,3- triazole ⁇ -amino acid.
  • the invention also provides compositions of peptides or polypeptides having at least one 1,2,3-triazole ⁇ -amino acid.
  • Formula I provides an example of a 1,2,3- triazole ⁇ -amino acid.
  • R is any amino acid side chain; Ri is H, a protecting group or an amino acid; and R 2 is H, a protecting group or an amino acid.
  • amino acid includes the residues of the natural ⁇ -amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyb Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well as ⁇ -amino acids, 1,2,3-triazole ⁇ -amino acids, synthetic and unnatural amino acids. Many types of amino acid residues are useful in the cyclic peptides and the invention is not limited to natural, genetically-encoded amino acids.
  • ⁇ -amino acids e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyb Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val
  • amino acids that can be utilized in the cyclic peptide described herein can be found, for example, in Fasman, 1989, CRC Practical Handbook of Biochemistry and Molecular Biology, CRC Press, Inc., and the references cited therein. Another source of a wide variety of amino acid residues is provided by the website of RSP Amino Acids Analogues, Inc. (www.amino-acids.com).
  • protecting group includes any substituent, moiety, and the like which can protect a potentially reactive functional group from one or more undesired chemical transformation.
  • a protecting group can, for example, exist as any temporary adduct (e.g. covalent attachment) to a target molecule that can be selectively removed either a chemical or enzymatic method.
  • Suitable protecting groups encompass any described in the literature, or later developed, including those described in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G.
  • Nanotube or “nanotubule” is a small tubule that may spontaneously form from the 1,2,3-triazole ⁇ -amino acids and peptides of the present invention.
  • the present cyclic peptides are believed to stack to form supramolecular structures composed of nanotubes.
  • Nanotubes and molecular structures described herein may be used as membrane channels, for example to facilitate ion and small molecule transport.
  • the 1,2,3-triazole ⁇ -amino acids and peptides can be employed as drug carriers and agents for the delivery or modulation of small molecule transport in and between cells.
  • Hydrogen bonding between peptides is believed to help drive the self-assembly of the supramolecular structures from cyclic peptides.
  • Each nanotube has a pore in the center of the tube that is surrounded by the series of peptide backbones of the stacked cyclic peptides that form the nanotubes. The size of the pore depends upon the number of amino acids in the cyclic peptides that form the nanotube.
  • ions, sugars, and other small molecules can travel through the pores of the nanotubes. Larger molecules can also flow through pores formed from larger cyclic peptides and supramolecular structures formed of aggregates of nanotubes.
  • the supramolecular structure is thought to be a barrel-like structure composed of clusters of nanotubes.
  • the supramolecular structure is thought to be a "carpet” or “carpet-like” arrangement of nanotubes.
  • a “carpet” or “carpet-like” arrangement of one or more nanotubes is where the nanotube(s) adopt orientations that can be approximately or somewhat parallel to the plane of the membrane structure.
  • the nanotubes can assume other orientations relative to the plane of the membrane.
  • the nanotubes may be situated on the surface of the membrane, or may be partially or fully contained within the interior of the membrane.
  • the carpet-like nanotubes can be oriented with a tilt angle of up to approximately 70 ⁇ 5° from the membrane normal.
  • a hydrophilic face of a nanotube can, for example, be positioned so that it is in contact with the hydrophilic portions of the membrane or with the aqueous environment.
  • a hydrophobic face of a nanotube can, for example, be in contact with the hydrophobic portions of the membrane.
  • Supramolecular structures may be contrasted with molecular or polymeric systems in which the products are based on covalent bond formation between reactants or monomers.
  • the proposed peptide supramolecular structures are thermodynamically controlled assemblies that can undergo reversible structural assembly and disassembly. Such assembly-disassembly will depend, for example, on the environment, subunit structure, side group selection, side group interaction, and the nature and combination of noncovalent forces operating on the system.
  • covalent polymeric structures have been used to design kinetically stable structures rather than structures that assemble and dissemble in response to the environment.
  • one attractive feature of the present compositions containing peptides that can form supramolecular structures is their ability to select amongst various cell membrane types.
  • substantially no hemolysis can mean that less than about 20%, alternatively less than 15% or less than 10%, no undesirable, or no detectable, hemolysis at the tested or desired peptide dosage or concentration has occurred.
  • substantially no toxicity or lysis can mean that less than about 20%, alternatively less than 15% or less than 10%, no undesirable, or no detectable, toxicity or lysis at the tested or desired peptide dosage or concentration has occurred.
  • substantially no hemolysis, toxicity or lysis means that less than about 5%, or no detectable, hemolysis, toxicity or lysis, etc., at the tested or desired peptide dosage or concentration has occurred.
  • 1,2,3-TriazoIe ⁇ - Amino Acids The present invention provides 1,2,3-triazole ⁇ -amino acids, for example, 1,2,3- triazole ⁇ -amino acids having Formula I.
  • R is any amino acid side chain; Ri is H, a protecting group or an amino acid; and R 2 is H, a protecting group or an amino acid.
  • the R amino acid side chains can be any natural or synthetic side chain known to one of skill in the art.
  • the 1,2,3-triazole ⁇ -amino acids can have R groups such as hydroxy; linear or branched C ⁇ -C 6 -alkyb alkenyb alkynyl; hydroxy-C ⁇ -C 6 -alkyl; amino-Ci-Ce-alkyl; Ci-C ⁇ -alkyloxy, Ci-C ⁇ -alkoxy-alkyl; -C ⁇ - amino; mono- or di-Ci-C ⁇ -alkylamino; carboxamido; carboxamido-C ⁇ -C 6 -alkyl; sulfonamido; sulfonamido-C ⁇ -C 6 -alkyb urea, cyano, fluoro,
  • the present invention provides peptides and polypeptides having at least one 1,2,3- triazole ⁇ -amino acid.
  • the invention also provides compositions of peptides or polypeptides having at least one 1,2,3-triazole ⁇ -amino acid.
  • Such peptides and polypeptides can be linear or cyclic.
  • the invention provides cyclic peptides that have at least one 1,2,3-triazole ⁇ -amino acid and an amino acid sequence of alternating D- and L-amino acids that is between four to about sixteen, alternatively about six to about sixteen amino acids in length.
  • the cyclic peptides of the present invention can have at least one 1,2,3- triazole ⁇ -amino acid and between three to about ten ⁇ -amino acids.
  • the cyclic D, L-peptides do not include the amino acids proline and glycine.
  • ⁇ - amino acids can be substituted at the ⁇ - or ⁇ -carbons, or both.
  • Mono-substituted ⁇ -amino acids of either S or R chirality can be employed for the construction of cyclic ⁇ -peptides, provided that the cyclic beta peptide is homochirab Disubstituted ⁇ -amino acids employed in the present invention must have the relative R,R or S,S diastereomeric configuration, provided that the ⁇ -amino acid residues in a cyclic peptide structure are homochirab Cyclic peptides having ⁇ -amino acids generally have at least one ⁇ -amino acid with at least one polar side chain.
  • the cyclic peptides of the present invention are believed to undergo self-assembly to form supramolecular structures that, upon assembly in or on a microbial, fungal or cancer cell membrane, or in association with a virus or viral membrane, can cause depolarization and/or permeablization and/or destabilization of the microbial, fungal, or cancer cell membrane, or virus.
  • the cyclic peptides cause death, for example, by lysis, of the microbial cell, fungal cell, or cancer cell or virus.
  • Peptides of the present invention can be made from at least one 1,2,3-triazole ⁇ -amino acid and can include ⁇ -amino acids or ⁇ -amino acids.
  • the amino acid sequence of cyclic peptides includes at least one polar amino acid in the case of D,L-amino acid cyclic peptides, or at least one polar side chain in the case of cyclic ⁇ -peptides.
  • the percentage of polar amino acids can range, for example, from about 25% or 33% to about 65% or 88%. However, in some embodiments a majority of the amino acids are polar. For example, the percentage of polar amino acids can be from about 50% to about 88%) of the total number of amino acids. The exact number of polar and nonpolar amino acids depends on the size and the properties sought for a given cyclic peptide.
  • the size of the cyclic peptides is about six to about ten D,L-amino acids or three to about ten ⁇ -amino acids. In other embodiments, the size for the present cyclic peptides is about six to about eight D,L- amino acids or four to about six ⁇ -amino acids.
  • an eight residue cyclic peptide of the invention can have at least one, alternatively, two to seven polar D- and/or L- amino acids.
  • Other eight residue cyclic peptides will have three to five polar D- and/or L- amino acids for example.
  • Preferred eight residue cyclic peptides have three, four or five polar amino acids.
  • six residue cyclic peptides of the invention can have two to five polar D- and/or L-amino acids.
  • Other six residue cyclic peptides may have three to four polar D- and/or L-amino acids. At least one of these polar D- or L-amino acids may be adjacent to at least one other polar D- or L-amino acid. Alternatively, at least one polar D- or L-amino acid may be adjacent only to nonpolar D- or L- amino acids.
  • Beta peptides having about four to about eight ⁇ -amino acids may have, for example, about two to twelve polar side chains, depending on the level of ⁇ and ⁇ backbone substitution.
  • the cyclic D- L-peptides of the invention generally have about 25% to about 88% ionizable amino acid residues.
  • the percentage of ionizable amino acids can be from about 33% or 50% to about 65% or 88%) of the total number of D- and/or L- amino acids.
  • a six or eight residue cyclic peptide can have at least one, or alternatively two or three or more ionizable D- and/or L-amino acids.
  • the cyclic peptides of the invention can have four to six ionizable D- and/or L-amino acids.
  • Such an ionizable D- or L-amino acid can be adjacent to at least one other polar or ionizable D- or L-amino acid.
  • the cyclic peptides of the invention can have at least one ionizable D- or L-amino acid that is adjacent only to nonpolar D- or L-amino acids.
  • the cyclic ⁇ -peptides of the invention generally have about 25%) to about 88% ionizable amino acid side chains.
  • the percentage of ionizable amino acid side chains can be from about 33% or 50% to about 65%) or 88%> of the total number of amino acid side chains.
  • a four to six residue cyclic ⁇ -peptide can have at least one, or alternatively two or three or more ionizable amino acid side chains.
  • the cyclic ⁇ - peptides of the invention can have four to six ionizable amino acid side chains.
  • the cyclic peptides of the invention can have nonpolar D- and/or L-amino acid residues.
  • the number of non-polar amino acids chosen can vary as the size of the peptide varies and as the selected target membrane (e.g. microbial, fungal, cancer cell) environment, or virus or viral membrane, varies.
  • the cyclic peptides of the invention generally have about 12%) to about 75%) D- and L-nonpolar amino acids.
  • the percentage of nonpolar amino acids can be from about 50%) to about 67%> or 75% of the total number of D- and L-amino acids.
  • an eight residue cyclic peptide of the invention can have at least one, alternatively, two to seven nonpolar D- and/or L-amino acids.
  • Other eight residue cyclic peptides may have three to five nonpolar D- and/or L-amino acids.
  • six residue cyclic peptides of the invention have two to five nonpolar D- and/or L-amino acids.
  • Other six residue cyclic peptides may have three to four nonpolar D- and/or L-amino acids.
  • At least one of these nonpolar D- or L-amino acids may be adjacent to at least one other nonpolar D- or L-amino acid.
  • at least one nonpolar D- or L-amino acid may be adjacent only to polar D- or L-amino acids.
  • the cyclic peptides do not include the amino acid proline or glycine, but certain cyclic peptides may have good activity even though proline or glycine is included.
  • ⁇ -amino acids can have non-polar side chains at the ⁇ - or ⁇ -carbons, or both. The number of non-polar amino acid side chains chosen can vary as the size of the peptide varies and as the selected target or target membrane environment varies.
  • the cyclic ⁇ -peptides of the invention generally have about 12% to about 75% nonpolar amino acid side chains.
  • the percentage of nonpolar amino acid side chains can be from about 50% ⁇ to about 67%> or 75% of the total number of amino acid side chains.
  • an eight residue cyclic ⁇ -peptide of the invention can have at least one, alternatively, two to seven nonpolar amino acid side chains.
  • Other eight residue cyclic ⁇ -peptides may have three to five nonpolar amino acid side chains.
  • six residue cyclic ⁇ -peptides of the invention have two to five nonpolar amino acid side chains.
  • Other six residue cyclic ⁇ -peptides may have three to four nonpolar amino acid side chains.
  • peptides and polypeptides of the invention have at least one 1,2,3-triazole ⁇ - amino acid, they can also contain a variety of other amino acids.
  • Amino acids used in the peptides and polypeptides of the invention can be genetically encoded amino acids, naturally occurring non-genetically encoded amino acids, or synthetic amino acids. Both L- and D- enantiomers of any of the above are utilized in cyclic peptides.
  • the amino acid notations used herein for the twenty genetically encoded L-amino acids and some examples of non- encoded amino acids are provided in Table 1. Table 1
  • Certain commonly encountered amino acids that are not genetically encoded and that can be present in the peptides of the invention include, but are not limited to, ⁇ -alanine (b- Ala) and other omega-amino acids such as 3-aminopropionic acid (Dap), 2,3- diaminopropionic acid (Dpr), 4-aminobutyric acid and so forth; ⁇ -aminoisobutyric acid (Aib); ⁇ -aminohexanoic acid (Aha); ⁇ -aminovaleric acid (Ava); methylglycine (MeGly); ornithine (Orn); citrulline (Cit); t-butylalanine (t-BuA); t-butylglycine (t-BuG); N-methylisoleucine (Melle); phenylglycine (Phg); cyclohexylalanine (Cha); norleucine (Nle); 2-naphthylalanine (2-N
  • Additional amino acid analogs contemplated include phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, ⁇ - methyl-alanine, para-benzoyl-phenylalanine, propargylglycine, and sarcosine.
  • Peptides that are encompassed within the scope of the invention can have any of foregoing amino acids in the L- or D- configuration, or any other amino acid known to one of skill in the art. Amino acids that are substitutable for each other generally reside within similar classes or subclasses.
  • amino acids can be placed into different classes depending primarily upon the chemical and physical properties of the amino acid side chain. For example, some amino acids are generally considered to be hydrophilic or polar amino acids and others are considered to be hydrophobic or nonpolar amino acids.
  • Polar amino acids include amino acids having acidic, basic or hydrophilic side chains and nonpolar amino acids include amino acids having aromatic or hydrophobic side chains.
  • Nonpolar amino acids may be further subdivided to include, among others, aliphatic amino acids.
  • the definitions of the classes of amino acids as used herein are as follows: "Nonpolar Amino Acid" refers to an amino acid having a side chain that is uncharged at physiological pH, that is not polar and that is generally repelled by aqueous solution.
  • Examples of genetically encoded hydrophobic amino acids include Ala, He, Leu, Met, Trp, Tyr and Val.
  • non-genetically encoded nonpolar amino acids include t-BuA, Cha and Nle.
  • “Aromatic Amino Acid” refers to a nonpolar amino acid having a side chain containing at least one ring having a conjugated ⁇ -electron system (aromatic group). The aromatic group may be further substituted with substituent groups such as alkyl, alkenyb alkynyl, hydroxyb sulfonyb nitro and amino groups, as well as others.
  • Examples of genetically encoded aromatic amino acids include phenylalanine, tyrosine and tryptophan.
  • Non-genetically encoded aromatic amino acids include phenylglycine, 2-naphthylalanine, ⁇ -2-thienylalanine, l,2,3,4-tetrahydroisoquinoline-3- carboxylic acid, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylaIanine and 4- fluorophenylalanine.
  • “Aliphatic Amino Acid” refers to a nonpolar amino acid having a saturated or unsaturated straight chain, branched or cyclic hydrocarbon side chain. Examples of genetically encoded aliphatic amino acids include Ala, Leu, Val and He. Examples of non- encoded aliphatic amino acids include Nle.
  • Polar Amino Acid refers to a hydrophilic amino acid having a side chain that is charged or uncharged at physiological pH and that has a bond in which the pair of electrons shared in common by two atoms is held more closely by one of the atoms.
  • Polar amino acids are generally hydrophilic, meaning that they have an amino acid having a side chain that is attracted by aqueous solution.
  • genetically encoded polar amino acids include asparagine, cysteine, glutamine, lysine and serine.
  • non-genetically encoded polar amino acids include citrulline, homocysteine, N-acetyl lysine and methionine sulfoxide.
  • Acidic Amino Acid refers to a hydrophilic amino acid having a side chain pK value of less than 7. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of a hydrogen ion. Examples of genetically encoded acidic amino acids include aspartic acid (aspartate) and glutamic acid (giutamate). “Basic Amino Acid” refers to a hydrophilic amino acid having a side chain pK value of greater than 7. Basic amino acids typically have positively charged side chains at physiological pH due to association with hydronium ion. Examples of genetically encoded basic amino acids include arginine, lysine and histidine.
  • non-genetically encoded basic amino acids include the non-cyclic amino acids omithine, 2,3- diaminopropionic acid, 2,4-diaminobutyric acid and homoarginine.
  • “Ionizable Amino Acid” refers to an amino acid that can be charged at a physiological pH.
  • Such ionizable amino acids include acidic and basic amino acids, for example, D-aspartic acid, D-glutamic acid, D-histidine, D-arginine, D-lysine, D-hydroxylysine, D-ornithine, L-aspartic acid, L-glutamic acid, L-histidine, L-arginine, L-lysine, L- hydroxyl sine or L-ornithine.
  • the above classifications are not absolute.
  • Several amino acids exhibit more than one characteristic property, and can therefore be included in more than one category.
  • tyrosine has both a nonpolar aromatic ring and a polar hydroxyl group.
  • tyrosine has several characteristics that could be described as nonpolar, aromatic and polar. However, the nonpolar ring is dominant and so tyrosine is generally considered to be nonpolar. Similarly, in addition to being able to form disulfide linkages, cysteine also has nonpolar character. Thus, while not strictly classified as a hydrophobic or nonpolar amino acid, in many instances cysteine can be used to confer hydrophobicity or nonpolarity to a peptide.
  • Table 2 The classifications of the above-described genetically encoded and non-encoded amino acids are summarized in Table 2, below.
  • Table 2 is for illustrative purposes only and does not purport to be an exhaustive list of amino acid residues that may comprise the peptides and peptide analogues described herein.
  • Other amino acid residues that are useful for making the peptides described herein can be found, e.g., in Fasman, 1989, CRC Practical Handbook of Biochemistry and Molecular Biology, CRC Press, Inc., and the references cited therein.
  • Another source of amino acid residues is provided by the website of RSP Amino Acids Analogues, Inc. (www.amino-acids.com).
  • Amino acids not specifically mentioned herein can be conveniently classified into the above- described categories on the basis of known behavior and/or their characteristic chemical and/or physical properties as compared with amino acids specifically identified.
  • polar amino acids contemplated by the present invention include, for example, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, homocysteine, lysine, hydroxylysine, ornithine, serine, threonine, the corresponding ⁇ -amino acids, and structurally related amino acids.
  • the polar amino is an ionizable amino acid such as arginine, aspartic acid, glutamic acid, histidine, hydroxylysine, lysine, or ornithine.
  • nonpolar or nonpolar amino acid residues examples include, for example, alanine, valine, leucine, methionine, isoleucine, phenylalanine, tryptophan, tyrosine and the like.
  • the amino acid sequence of a peptide can be modified so as to result in a peptide variant that includes the substitution of at least one amino acid residue in the peptide for another amino acid residue, including substitutions that utilize the D rather than L form.
  • One or more of the residues of the peptide can be exchanged for another, to alter, enhance or preserve the biological activity of the peptide.
  • Such a variant can have, for example, at least about 10% of the biological activity of the corresponding non-variant peptide.
  • Conservative amino acid substitutions are often utilized, i.e., substitutions of amino acids with similar chemical and physical properties, as described above.
  • conservative amino acids substitutions involve exchanging aspartic acid for glutamic acid; exchanging lysine for arginine or histidine; exchanging one nonpolar amino acid (alanine, isoleucine, leucine, methionine, phenylalanine, tryptophan, tyrosine, valine) for another; and exchanging one polar amino acid (aspartic acid, asparagine, glutamic acid, glutamine, glycine, serine, threonine, etc.) for another.
  • the substitutions are introduced, the variants are screened for biological activity.
  • the present isolated, purified peptides or variants thereof can be synthesized in vitro, e.g., by the solid phase peptide synthetic method or by enzyme catalyzed peptide synthesis or with the aid of recombinant DNA technology.
  • Solid phase peptide synthetic method is an established and widely used method, which is described in references such as the following: Stewart et ab, Solid Phase Peptide Synthesis. W. H. Freeman Co., San Francisco (1969); Merrifield, J. Am. Chem. Soc. 852149 (1963); Meienhofer in "Hormonal Proteins and Peptides/' ed.; CH.
  • the cyclic peptides of the invention can have an amino acid sequence having formula LI:
  • each p, q, or r is separately an integer of 1 or 0; at least one p is 1; X is an epsilon amino acid residue of the following formula:
  • R 3 , R , and R 5 are separately any amino acid, functional group, protecting group,; each Y is any ⁇ amino acid residue; each Z is any ⁇ amino acid residue; and Ri and R 2 can separately be a hydrogen atom, hydroxy group, protecting group or Ri and R 2 can be linked to form a cyclic peptide when there are at least three residues in the peptide.
  • R5 is an amino acid.
  • R 3 and j are chiral propargyl amines. Example of synthesis of chiral propargylamines are provided in Rae, Alastair; Ker, James; Tabor, Alethea B.; Castro, Jose L.; Parsons, Simon. Tetrahedron Letters 1998, 39(36), 6561-6564, which is incorporated by reference herein.
  • Cyclic peptides capable of self assembly the invention provides cyclic peptides that can self-assembly into supramolecular structures.
  • self-assembling peptides of the invention can have an amino acid sequence having formula HI: cyclorXrY ⁇ X.Na] III wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • such self-assembling peptides of the invention can have an amino acid sequence having formula IV: cycloL ZrX Z ⁇ IV
  • each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Z is a ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acids and where each Z has the same chirality as the all the other Z groups.
  • such self-assembling peptides of the invention can have an amino acid sequence having formula V: cyclo[X X 2 - X 3 ] V
  • each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups.
  • such self-assembling peptides of the invention can have an amino acid sequence having formula VI: cyclo[X r X 2 - X 3 - X 4 ] VI wherein each X is separately an ⁇ amino acid with alternating R,R or S,S substitution pattern throughout the peptide.
  • such self-assembling peptides of the invention can have an amino acid sequence having formula VII: cycloCXrYi-Ya-Xz-Ya-Yi] VII
  • each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • such self-assembling peptides of the invention can have an amino acid sequence having formula VIII: cyclo[X ⁇ -Y ⁇ -Y 2 -X 2 -Y 3 N 4 -X 3 -Y 5 -Y6] VIII wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula IX: R (X 1 )p-(Y 1 ) q -(Z 1 )r-(X 2 )p-(Y 2 )q-(Z 2 ) r - ...-(Xn)p-(Yn)q-(Z n ) r -X-R 2 IX wherein: each p, q, or r is separately an integer of 1 or 0; at least one p is 1; X is an epsilon amino acid residue of the following formula:
  • R 3 , R 4 , and R 5 are separately any amino acid, functional group, protecting group; each Y is any amino acid residue; each Z is any ⁇ amino acid residue; and Ri and R 2 can separately be a hydrogen atom, hydroxy group, protecting group or Ri and R 2 can be linked to form a cyclic peptide when there are at least two residues in the peptide.
  • R 5 is an amino acid.
  • R 3 and t are chiral propargyl amines.
  • the invention also provides a cyclic peptide that has an amino acid sequence comprising formula X: cyclo[X ⁇ -YrX2-Y2-X3-Y3] X wherein: each X is an ⁇ amino acid as described above with either an R,R or S,S chirality and where each X has the same chirality as the all the other X groups; and each Y is an ⁇ amino acid with either R or S chirality, but with chirality opposite to that of the X ⁇ amino acid and where each Y has the same chirality as the all the other Y groups.
  • cyclic peptides are utilized.
  • linear peptides or polypeptides are utilized.
  • libraries of peptides can be made using a one-bead-one-compound strategy provided by Lam et al. (97 Chem. Rev. 411-448 (1997) or synthesized on macrobeads by a split and pool method of Furka, et al. (37 Int. J. Pept. Prot.
  • Mass spectrometric sequence analysis techniques enable rapid identification of every peptide within a given library. See, Biemann, K. 193 Methods Enzymol. 455 (1990).
  • synthetic operations including peptide cyclization, are performed on solid support to avoid laborious and difficult to automate solution-phase operations.
  • the final product of the synthesis regimen is generally sufficiently pure for biological assays without laborious purification procedures. Peptide yields from each synthesis can be sufficient for performing 50 to 100 assays. Rapid, automatic mass-spectrometry-based peptide sequence analysis can be performed to identify peptide sequences that have high activity and to discard peptide sequences with low activity.
  • the synthetic approach employed can provide individually separable and identifiable peptide sequences to avoid the use of combinatorial library mixtures and laborious deconvolution techniques.
  • libraries of impure mixtures of peptides can also be generated for testing.
  • Impure preparations of peptides can be used for quick screening of combinations of sequences. When a mixture of peptides shows activity, the peptides in the mixture can either be individually isolated and tested or pure peptides having sequences known to be present in the impure mixture can be individually prepared and tested.
  • Salts of carboxyl groups of a peptide or peptide variant of the invention may be prepared in the usual manner by contacting the peptide with one or more equivalents of a desired base such as, for example, a metallic hydroxide base, e.g., sodium hydroxide; a metal carbonate or bicarbonate base such as, for example, sodium carbonate or sodium bicarbonate; or an amine base such as, for example, triethylamine, triethanolamine, and the like.
  • a desired base such as, for example, a metallic hydroxide base, e.g., sodium hydroxide
  • a metal carbonate or bicarbonate base such as, for example, sodium carbonate or sodium bicarbonate
  • an amine base such as, for example, triethylamine, triethanolamine, and the like.
  • N-acyl derivatives of an amino group of the peptide or peptide variants may be prepared by utilizing an N-acyl protected amino acid for the final condensation, or by acylating
  • O-acyl derivatives may be prepared, for example, by acylation of a free hydroxy peptide or peptide resin. Either acylation may be carried out using standard acylating reagents such as acyl halides, anhydrides, acyl imidazoles, and the like. Both N-acylation and O-acylation may be carried out together, if desired. Acid addition salts of the peptide or variant peptide, or of amino residues of the peptide or variant peptide, may be prepared by contacting the peptide or amine with one or more equivalents of the desired inorganic or organic acid, such as, for example, hydrochloric acid.
  • Esters of carboxyl groups of the peptides may also be prepared by any of the usual methods known in the art.
  • the invention also contemplates cyclic and linear peptides with at least one 1,2,3- triazole ⁇ -amino acid that are also composed of one or more ⁇ amino acids.
  • Such ⁇ -amino acids can be substituted along their peptide backbones by one to two substituents.
  • substituents can include cycloalkyl, cycloalkenyl, and heterocylic rings that encompass the ⁇ and ⁇ carbons of the ⁇ -peptide backbone.
  • These rings can be, for example, C 3 -C 8 cycloalkyl, cycloalkenyl or heterocyclic rings having one or more nitrogen atoms as the sole heteroatom, and can be substituted or unsubstituted.
  • the substituents on the ring or on the ⁇ and ⁇ carbons of the ⁇ -peptide can be, for example, hydroxy, linear or branched C ⁇ -C 6 -alkyb alkenyb alkynyl; hydiOxy-C ⁇ -C 6 -alkyl; amino-C ⁇ -C 6 -alkyl; C ⁇ -C 6 -alkyloxy, C ⁇ -C 6 -alkoxy- alkyl; -C ⁇ - amino; mono- or di-Ci-C ⁇ -alkylamino; carboxamido; carboxamido-C ⁇ -C 6 - alkyl; sulfonamido; sulfonamido-C ⁇ -C 6
  • the present invention provides small peptides and compositions that selectively kill or inhibit the growth of target cells or organisms, preferably without substantial or undesired toxicity toward normal mammalian cells.
  • the present invention includes cyclic peptides, and pharmaceutical compositions comprising cyclic peptides with at least one 1,2,3-triazole ⁇ - amino acid, and with either a sequence of alternating D-, and L- ⁇ -amino acids, a sequence of alternating ⁇ -amino acids and ⁇ -amino acids, or a sequence of ⁇ -amino acids, that have flat, ring-shaped conformations.
  • Such ring-shaped conformations project the amino acid side chains of the cyclic peptides away from the center of the ring and orient the amide backbone approximately perpendicular to the plane of the ring structure. It is believed that under conditions that favor hydrogen bonding, such as side chain charge neutralization through interactions with cell membrane constituents and/or contact with low dielectric constant environments of cell membranes, the cyclic peptides can self-assemble via intermolecular hydrogen bonding to form supramolecular structures. Cyclic peptides that simply contain one or more D-amino acids do not adopt a flat ring-shaped conformation and do not have the backbone conformation needed for self-assembly of the cyclic peptide into supramolecular structures.
  • Target microbial organisms against which the present cyclic peptides are effective include microbes, including any single cell organism or parasite that has a cellular membrane and that can infect a mammal.
  • target microbial organisms include bacteria, helminths, protozoa, yeast strains and other single cell organisms.
  • Targets include both gram-negative and gram-positive bacteria, as well as fungal and cancer cell types, and viruses.
  • Differences in environment for example, the difference in composition of different cellular membranes, can be relied on to influence the course and nature of the proposed assembly process.
  • This feature is used in the present invention both to target and to optimize the anti-microbial, anti-fungal, anti-viral or anti-cancer activity of selected cyclic peptides against particular microbial species or cancer cells or other target cells, while providing substantially no toxicity, or no undesired toxicity, in normal mammalian cells at therapeutically effective doses and dose regimens.
  • Supramolecular structures are believed to respond to their immediate environment through dynamic self-assembling/disassembling processes to quickly find the most thermodynamically favored assembly. It is believed that, during assembly, peptide supramolecular structures sense and respond to the environment of a cellular membrane by sampling various topologically related assemblies.
  • the preferred cyclic peptides of the invention do not or cannot adopt a thermodynamically favorable supramolecular structure.
  • mammalian membranes are not substantially or undesirably affected by the presence of such cyclic peptides.
  • the present cyclic peptides are believed to form unique energetically favorable supramolecular structures that destabilize (e.g., lyse), permeabilize and/or depolarize the microbial or cancer cell membrane, thereby disrupting microbial transmembrane ion and electrical gradients and other vital functions, and quickly leading to cell death.
  • Changes in amino acid sequence of a cyclic peptide can be utilized to create differences at the supramolecular level.
  • changes in the structure of a cyclic peptide may constrain peptide interaction and limit formation of supramolecular structures to particular cellular membranes that have particular membrane constituents, membrane partitioning properties, uptake properties, and the like.
  • Another feature of the present self-assembling peptide supramolecular structures is believed to be the potential for a given cyclic peptide to form a number of diastereomeric nanotube assemblies. This property stems from the fact that backbone-backbone hydrogen bonding are believed primarily to direct the self-assembly of the nanotube structure.
  • Differently stacked subunits can give rise to topoisomeric supramolecular structures that share the same or nearly the same tubular ⁇ -sheet-like hydrogen bonded backbone structure.
  • the variety of supramolecular structures assembled from a single cyclic peptide minimizes the probability that microbes or cancer cells can develop resistance to these agents.
  • a multitude of cyclic peptides can quickly be screened or evaluated for the ability to selectively target and assemble in microbial, fungal, or cancer cell membranes.
  • therapeutic agents can be linked to the linear or cyclic peptides and polypeptides of the invention, for example, through at least one 1,2,3-triazole ⁇ -amino acid present in the peptide or polypeptide.
  • therapeutic agents can be any therapeutic agent available to one of skill in the art.
  • the therapeutic agent can be a small molecule, a peptide, a polypeptide, a glycoprotein, a lipoprotein or a nucleic acid.
  • the therapeutic agent can be an anti-cancer agent, an anti-microbial agent, an anti-inflammatory agent, a pain reliever, an antihistamine, a bronchodilator or other agent.
  • an antibiotic can be linked to the peptides of the invention, such as aminoglycosides (e.g., streptomycin, gentamicin, sisomicin, tobramycin and amicacin), ansamycins (e.g. rifamycin), antimycotics (e.g. polyenes and benzofuran derivatives), ⁇ -lactams (e.g.
  • penicillins and cephalosporins include chloramphenical (including thiamphenol and azidamphenicol), linosamides (lincomycin, clindamycin), macrolides (erythromycin, oleandomycin, spiramycin), polymyxins, bacitracins, tyrothycin, capreomycin, vancomycin, tetracyclines (including oxytetracycline, minocycline, doxycycline), phosphomycin and fusidic acid.
  • peptides or polypeptides of the invention are administered so as to achieve a reduction in at least one symptom associated with an infection, indication or disease, or a decrease in the amount of antibody associated with the indication or disease.
  • the peptide, a variant thereof or a combination thereof may be administered as single or divided dosages, for example, of at least about 0.01 mg/kg to about 500 to 750 mg/kg, of at least about 0.01 g/kg to about 300 to 500 mg/kg, at least about 0.1 mg/kg to about 100 to 300 mg/kg or at least about 1 mg/kg to about 50 to 100 mg/kg of body weight, or at least about 1 mg/kg to about 20 mg/kg of body weight, although other dosages may provide beneficial results.
  • the amount administered will vary depending on various factors including, but not limited to, the peptide chosen, the disease, the weight, the physical condition, the health, the age of the mammal, whether prevention or treatment is to be achieved, and if the peptide is chemically modified. Such factors can be readily determined by the clinician employing animal models or other test systems that are available in the art. Administration of the therapeutic agents in accordance with the present invention may be in a single dose, in multiple doses, in a continuous or intermittent manner, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors l ⁇ iown to skilled practitioners.
  • the administration of the peptides of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses. Both local and systemic administration is contemplated.
  • To prepare the composition peptides are synthesized or otherwise obtained, purified as necessary or desired and then lyophilized and stabilized. The peptide can then be adjusted to the appropriate concentration, and optionally combined with other agents.
  • the absolute weight of a given peptide included in a unit dose can vary widely. For example, about 0.01 to about 2 g, or about 0.1 to about 500 mg, of at least one peptide of the invention, or a plurality of peptides specific for a particular cell type can be administered.
  • the unit dosage can vary from about 0.01 g to about 50 g, from about 0.01 g to about 35 g, from about 0.1 g to about 25 g, from about 0.5 g to about 12 g, from about 0.5 g to about 8 g, from about 0.5 g to about 4 g, or from about 0.5 g to about 2 g.
  • Daily doses of the cyclic peptides of the invention can vary as well.
  • Such daily doses can range, for example, from about 0.1 g/day to about 50 g/day, from about 0.1 g/day to about 25 g/day, from about 0.1 g/day to about 12 g/day, from about 0.5 g/day to about 8 g/day, from about 0.5 g/day to about 4 g/day, from about 0.5 g/day to about 1 g/day, and from about 0.5 g/day to about 2 g/day.
  • one or more suitable unit dosage forms comprising the therapeutic peptides of the invention can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, dermal, transdermal, intrathoracic, intrapulmonary and intranasal (respiratory) routes.
  • the therapeutic peptides may also be formulated for sustained release (for example, using microencapsulation, see WO 94/ 07529, and U.S. Patent No.4,962,091).
  • the formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known to the pharmaceutical arts.
  • Such methods may include the step of mixing the therapeutic agent with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.
  • the therapeutic peptides of the invention are prepared for oral administration, they are generally combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form.
  • the peptides may be present as a powder, a granular formulation, a solution, a suspension, an emulsion or in a natural or synthetic polymer or resin for ingestion of the active ingredients from a chewing gum.
  • the active peptides may also be presented as a bolus, electuary or paste.
  • Orally administered therapeutic peptides of the invention can also be formulated for sustained release, e.g., the peptides can be coated, micro-encapsulated, or otherwise placed within a sustained delivery device.
  • the total active ingredients in such formulations comprise from 0.1 to 99.9% by weight of the formulation.
  • pharmaceutically acceptable it is meant a carrier, diluent, excipient, and/or salt that is compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • Pharmaceutical formulations containing the therapeutic peptides of the invention can be prepared by procedures known in the art using well-known and readily available ingredients.
  • the peptide can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, powders, aerosols and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include buffers, as well as fillers and extenders such as starch, cellulose, sugars, mannitob and silicic derivatives.
  • Binding agents can also be included such as carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone.
  • Moisturizing agents can be included such as glycerol, disintegrating agents such as calcium carbonate and sodium bicarbonate. Agents for retarding dissolution can also be included such as paraffin. Resorption accelerators such as quaternary ammonium compounds can also be included. Surface active agents such as cetyl alcohol and glycerol monostearate can be included. Adsorptive carriers such as kaolin and bentonite can be added. Lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols can also be included. Preservatives may also be added. The compositions of the invention can also contain thickening agents such as cellulose and/or cellulose derivatives.
  • tablets or caplets containing the peptides of the invention can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate.
  • Caplets and tablets can also include inactive ingredients such as cellulose, pre-gelatinized starch, silicon dioxide, hydroxy propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, corn starch, mineral oil, polypropylene glycol, sodium phosphate, zinc stearate, and the like.
  • Hard or soft gelatin capsules containing at least one peptide of the invention can contain inactive ingredients such as gelatin, microcrystalline cellulose, sodium lauryl sulfate, starch, talc, and titanium dioxide, and the like, as well as liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil.
  • enteric-coated caplets or tablets containing one or more peptides of the invention are designed to resist disintegration in the stomach and dissolve in the more neutral to alkaline environment of the duodenum.
  • the therapeutic peptides of the invention can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous, intraperitoneal or intravenous routes.
  • the pharmaceutical formulations of the therapeutic peptides of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension or salve.
  • the therapeutic peptides may be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion containers or in multi- dose containers.
  • preservatives can be added to help maintain the shelve life of the dosage form.
  • the active peptides and other ingredients may form suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active peptides and other ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen- free water
  • organic solvent(s) that is/are acceptable from the physiological standpoint, chosen, in addition to water, from solvents such as acetone, ethanob isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanob” polyglycols and polyethylene glycols, C1-C4 alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the name "Miglyob” isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes.
  • solvents such as acetone, ethanob isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanob” polyglycols and polyethylene glycols, C1-C4 alkyl esters of short-chain acids, ethyl or isopropyl lactate, fatty acid triglycerides such as the products marketed under the
  • an adjuvant chosen from antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic agents, perfumes, flavorings and colorings.
  • Antioxidants such as t-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene and ⁇ -tocopherol and its derivatives can be added.
  • combination products that include one or more peptides of the present invention and one or more other anti-microbial, anti-fungab anti-virab or anti-cancer agents.
  • antibiotics can be included in the pharmaceutical compositions of the invention, such as aminoglycosides (e.g., streptomycin, gentamicin, sisomicin, tobramycin and amicacin), ansamycins (e.g. rifamycin), antimycotics (e.g. polyenes and benzofuran derivatives), ⁇ -lactams (e.g.
  • aminoglycosides e.g., streptomycin, gentamicin, sisomicin, tobramycin and amicacin
  • ansamycins e.g. rifamycin
  • antimycotics e.g. polyenes and benzofuran derivatives
  • ⁇ -lactams e.g.
  • penicillins and cephalosporins include chloramphenical (including thiamphenol and azidamphenicol), linosamides (lincomycin, clindamycin), macrolides (erythromycin, oleandomycin, spiramycin), polymyxins, bacitracins, tyrothycin, capreomycin, vancomycin, tetracyclines (including oxytetracycline, minocycline, doxycycline), phosphomycin and fusidic acid. Additionally, the peptides are well suited to formulation as sustained release dosage forms and the like.
  • the formulations can be so constituted that they release the active peptide, for example, in a particular part of the intestinal or respiratory tract, possibly over a period of time.
  • Coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g., stents, catheters, peritoneal dialysis tubing, draining devices and the like.
  • the therapeutic agents may be formulated as is known in the art for direct application to a target area.
  • Forms chiefly conditioned for topical application take the form, for example, of creams, milks, gels, dispersion or microemulsions, lotions thickened to a greater or lesser extent, impregnated pads, ointments or sticks, aerosol formulations (e.g., sprays or foams), soaps, detergents, lotions or cakes of soap.
  • aerosol formulations e.g., sprays or foams
  • Other conventional forms for this purpose include wound dressings, coated bandages or other polymer coverings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols.
  • the therapeutic peptides of the invention can be delivered via patches or bandages for dermal administration.
  • the peptide can be formulated to be part of an adhesive polymer, such as polyacrylate or acrylate/vinyl acetate copolymer.
  • an adhesive polymer such as polyacrylate or acrylate/vinyl acetate copolymer.
  • the backing layer can be any appropriate thickness that will provide the desired protective and support functions.
  • a suitable thickness will generally be from about 10 to about 200 microns.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active peptides can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122; 4,383,529; or 4,051,842.
  • the percent by weight of a therapeutic agent of the invention present in a topical formulation will depend on various factors, but generally will be from 0.01% to 95% of the total weight of the formulation, and typically 0. l-85%> by weight.
  • Drops such as eye drops or nose drops, may be formulated with one or more of the therapeutic peptides in an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents.
  • Liquid sprays are conveniently delivered from pressurized packs. Drops can be delivered via a simple eye dropper-capped bottle, or via a plastic bottle adapted to deliver liquid contents dropwise, via a specially shaped closure.
  • the therapeutic peptide may further be formulated for topical administration in the mouth or throat.
  • the active ingredients may be formulated as a lozenge further comprising a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the composition of the present invention in a suitable liquid carrier.
  • the pharmaceutical formulations of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of the type that are available in the art. Examples of such substances include normal saline solutions such as physiologically buffered saline solutions and water.
  • the peptides of the invention can also be administered to the respiratory tract.
  • the present invention also provides aerosol pharmaceutical formulations and dosage forms for use in the methods of the invention.
  • dosage forms comprise an amount of at least one of the agents of the invention effective to treat or prevent the clinical symptoms of a specific infection, indication or disease.
  • the composition may take the form of a dry powder, for example, a powder mix of the therapeutic agent and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges, or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator, insufflator, or a metered- dose inhaler (see, for example, the pressurized metered dose inhaler (MDI) and the dry powder inhaler disclosed in Newman, S. P. in Aerosols and the Lung, Clarke, S. W. and Davia, D. eds., pp. 197-224, Butterworths, London, England, 1984).
  • Therapeutic peptides of the present invention can also be administered in an aqueous solution when administered in an aerosol or inhaled form.
  • aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable buffered saline solution containing between about 0.1 mg/ml and about 100 mg/ml of one or more of the peptides of the present invention specific for the indication or disease to be treated.
  • Dry aerosol in the form of finely divided solid peptide or nucleic acid particles that are not dissolved or suspended in a liquid are also useful in the practice of the present invention.
  • Peptides of the present invention may be formulated as dusting powders and comprise finely divided particles having an average particle size of between about 1 and 5 ⁇ m, alternatively between 2 and 3 ⁇ m. Finely divided particles may be prepared by pulverization and screen filtration using techniques well known in the art.
  • the particles may be administered by inhaling a predetermined quantity of the finely divided material, which can be in the form of a powder.
  • a predetermined quantity of the finely divided material which can be in the form of a powder.
  • the unit content of active ingredient or ingredients contained in an individual aerosol dose of each dosage form need not in itself constitute an effective amount for treating the particular infection, indication or disease since the necessary effective amount can be reached by administration of a plurality of dosage units.
  • the effective amount may be achieved using less than the dose in the dosage form, either individually, or in a series of administrations.
  • the therapeutic peptides of the invention are conveniently delivered from a nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Nebulizers include, but are not limited to, those described in U.S. Patent Nos. 4,624,251; 3,703,173; 3,561,444; and 4,635,627. Aerosol delivery systems of the type disclosed herein are available from numerous commercial sources including Fisons Corporation (Bedford, Mass.), Schering Corp. (Kenilworth, NJ) and American Pharmoseal Co., (Valencia, CA).
  • the therapeutic agent may also be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or metered-dose inhaler.
  • atomizers are the Mistometer (Wintrop) and the Medihaler (Riker).
  • the active ingredients may also be used in combination with other therapeutic agents, for example, pain relievers, anti-inflammatory agents, antihistamines, bronchodilators and the like, whether for the conditions described or some other condition.
  • the present invention further pertains to a packaged pharmaceutical composition for controlling microbial, fungal, or viral infections such as a kit or other container.
  • the kit or container holds a therapeutically effective amount of a pharmaceutical composition for controlling microbial infections and instructions for using the pharmaceutical composition for control of the microbial infection.
  • the pharmaceutical composition includes at least one peptide of the present invention, in a therapeutically effective amount such that microbial infection is controlled.
  • EXAMPLE 1 Materials and Methods General. 2-(lH-benzotriazole-l-yl)-bb3,3-tetramethyluronium hexafluorophosphate ( ⁇ BTU), benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), Fmoc-phenylalanine, leucine, and trityl chloride resin were purchased from Novabiochem. Trifluoromethanesulfonic anhydride was purchased from Lancaster. All other reagents were purchased from Aldrich or Fisher. All reagents and solvents were used as received unless otherwise noted.
  • ⁇ BTU 2-(lH-benzotriazole-l-yl)-bb3,3-tetramethyluronium hexafluorophosphate
  • PyBOP benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium he
  • Linear Peptide 8 (a) Loading of resin: Fmoc-phenylalanine (482 mg, 1.245 mmol) and diisopropylethylamine (0.217 mL, 1.245 mmol) were dissolved in CH 2 C1 2 (5 mL) and added to trityl chloride resin (500 mg, 1.66 mmol/g max loading). The mixture was agitated on a shaker for 4 hours. The vessel was then drained, and the resin was washed with 8:2: 1 CH 2 Cl 2 :MeOH:DIEA (2 x 10 min), CH 2 C1 2 (3 x 1 min), and Et 2 O. After drying under vacuum, loading was quantified by UV quantification of Fmoc release. Final loading was found to be 1.0 mmol/g.
  • the data set was 96%> complete and included 2356 reflections of which 320 were unique.
  • the scaling and averaging gave an Rmerg e of 7.4%.
  • the mean II a was 6.7, and the average multiplicity for the data set was 7.3.
  • Each cell contains l,EtOH (C 3 gH ⁇ N ⁇ o0 - C 2 H 6 0).
  • the structure was solved by molecular replacement and restrained refinement using the Collaborative Computational Project Number 4; Acta Cry tallogr. 1994, D50, 760-763; Xtalview: McRee, D. E. J. Mol. Graphics 1992, 10, 44-46.
  • the search model was generated from an energy-minimized structure of 1 calculated in the Discover module of InsightH.
  • Geometric restraints for the triazole portion were assembled from a survey of 1,4- disubstituted 1,2,3-triazoles in the Cambridge Structural Database. Hydrogen atoms were used in the refinement but were fixed to moving C, N, and O atoms. After several cycles of restrained refinement, electron density for the ethanol was located in a
  • a ⁇ represents the mole fraction of free monomer in solution
  • ⁇ ⁇ is the chemical shift of the proton in the monomer
  • ⁇ n is the chemical shift in aggregate species.
  • Equation 5 has only one real root subject to the physical constraints of the experiment, A value for a given pair of K 2 and K tripod can be determined explicitly for any experimental concentration.
  • experimental ⁇ ⁇ Qbs ⁇ , C) pairs for a given signal in the NMR spectrum can be used in equation 3 to find corresponding ⁇ ⁇ and ⁇ n by linear regression analysis.
  • K and K n were used as parameters in the above model to fit 5 0 b sd measured for nine protons in 1 at five concentrations in CDC1 3 .
  • the objective function was defined as the sum of the squares of the residuals between ⁇ 5 ca icd and t> 0 bsd for all signals.
  • Nonlinear numerical minimization algorithms were used to find the K 2 and K classroom values showing the best overall agreement with experimental data.
  • Atomic coordinates for 1 (CIF format). This material is available free of charge via the Internet at http://pubs.acs.org. See any current masthead page for ordering information and Web access instructions.
  • EXAMPLE 2 Peptides with 1,2,3-Triazole ⁇ -Amino Acids
  • the macroheterocyclic peptide 1 employed in the present study was designed based on similar structural considerations that have been previously noted for the cyclic D,L-R- peptide nanotube analogues. An even number of amino acids with alternating CR stereochemistry was employed to instill a preference for adoption of a flat ring conformation in solution. In this conformation the side chains are presented on the exterior of the macrocycle with the amide backbone oriented perpendicular to the plane of the ring. This provides complementary hydrogen bond donor and acceptor pairs on each face of the ring structure enabling cyclic peptide self-assembly.
  • Reagents used for Scheme 1 were as follows: (a) Fmoc-N-hydroxysuccinimide (71%); (b) (F 3 CS0 2 ) 2 O, ⁇ a ⁇ 3 , then CuS0 4 , K 2 C0 3 (84%); (c) 3, Cub diisopropylethylamine, 2,6- lutidine (97%).
  • Commercially available propargylamine (2) was protected as the N- fluorenylmethylcarbamate (3) by treatment with Fmoc-NHS. Tong, G.; Lawlor, J. M.; Tregear, G. W.; Haralambidis, J. J. Org. Chem. 1993, 58, 2223-2231.
  • Reagents used for Scheme 2 were as follows: (a) 20% piperidine/DMF; (b) 6, DIC, HOBT; (c) 20% piperidine/DMF; (d) Fmoc-Phe-OH, HBTU, DIEA; (e) 20% piperidine/DMF; (f) 6, DIC, HOBT; (g) 20% piperidine/DMF; (h) 5% TFA/DCM; (i) PyBOP, HOAT, DIEA. Solid phase Fmoc peptide synthesis was carried out using standard protocols except for coupling of the triazole residues which were performed under base free conditions to minimize racemization.
  • the linear peptide 8 was cleaved from the resin by treatment with 5% TFA/CH 2 C1 2 and purified by RP- HPLC (66% isolated yield). Exposure of the linear peptide in DMF to activating agents (PyBOP, HOAT, DIEA) resulted in a rapid macrolactamization yielding 1. Pure peptide 1 was isolated in 65% yield after repeated trituration/crystallization from water/MeCN. Techniques for synthesis of heterocychc amino acids with backbone modifications are well known in the art, examples and protocols of which are illustrated in Seneci, P.
  • the apparent equilibrium constants correspond to 6.1 kcalnnob 1 driving force for peptide dimerization and 6.2 kcal'mol "1 for each subunit added to from a higher order aggregate.
  • the aggregation propensity of peptide 1 was also evident by electrospray ionization mass spectrometry.
  • the triazole rings orient perpendicular to the overall macrocycle, lining the nanotube interior with ⁇ electron rich heteroaromatic moieties.
  • Three of the four amide bonds in the ring backbone form a network of intermolecular hydrogen bonds with N to O distances of 3.3 A.
  • the remaining amide bond is involved in an apparent ethanol-mediated bridging hydrogen bond with N to O and O to O distances of 2.7 A.
  • the portion of the amide backbone involved in this bridging hydrogen bond is slightly tilted, relative to the rest of the ring, with the amide N-H pointing more toward the ethanol oxygen than along the tube axis.
  • the peptide nanotube channel is roughly oval in shape with internal Van der Waals diameter ranging from 5.2 A between the triazole rings to 6.8 A between the phenylalanine ⁇ carbons.
  • Volume calculations were carried out using GRASP: Nicholls, A.; Sharp,; K. A.; Honig, B. Proteins 1991, 11, 281-296. These volume calculations suggest an approximately 80 A 3 cavity size per macrocycle repeat along the tube axis with the ethanol filling about 60% of this space.
  • Additional cyclic peptides with 1,2,3-triazole ⁇ -amino acids, including compounds II- XIII, from several genera of cyclic peptides were prepared as described above.
  • the invention describes the design, synthesis, and characterization of a new class of peptide based macrocycle incorporating 1,2,3-triazole ⁇ -amino acids in the backbone.
  • the synthesis is modular and straightforward with the protected triazole ⁇ -amino acid readily prepared from the corresponding free amino acid.
  • these molecules form a solvent filled nanotube held together by an extended network of intermolecular amide backbone hydrogen bonds.
  • NMR and mass spectrometry studies support similar behavior in solution and the gas phase.
  • an antibody includes a plurality (for example, a solution of antibodies or a series of antibody preparations) of such antibodies, and so forth.
  • the patent be interpreted to be limited to the specific examples or embodiments or methods specifically disclosed herein.
  • the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicants.
  • the terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intent in the use of such terms and expressions to exclude any equivalent of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed.

Abstract

L'invention porte sur des acides amino-1,2,3-triazole-e et sur des peptides et polypeptides en comportant au moins trois, lesdits peptides pouvant être linéaires ou cycliques. Dans certaines exécutions les peptides cycliques peuvent s'assembler pour former des structures supramoléculaires à usage thérapeutique ou pouvant servir au transport de petites molécules, ou à moduler le transport de petites molécules à l'intérieur de cellules ou entre des cellules.
PCT/US2004/022081 2003-07-09 2004-07-09 Acides amino triazole-$g(e) WO2005007675A2 (fr)

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EP2175512A1 (fr) * 2005-03-04 2010-04-14 Honeywell International Inc. Dispositif électrochimique
US7834038B2 (en) * 2005-11-09 2010-11-16 New York University Methods for preparing nonpeptidic oligomers from amino acids
US9175056B2 (en) 2006-12-14 2015-11-03 Alleron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US10328117B2 (en) 2006-12-14 2019-06-25 Aileron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US7960506B2 (en) 2006-12-14 2011-06-14 Aileron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US9675661B2 (en) 2006-12-14 2017-06-13 Aileron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US7981998B2 (en) 2006-12-14 2011-07-19 Aileron Therapeutics, Inc. Bis-sulfhydryl macrocyclization systems
US8609809B2 (en) 2006-12-14 2013-12-17 Aileron Thraputics, Inc. Bis-sulfhydryl macrocyclization systems
US9527896B2 (en) 2007-01-31 2016-12-27 Dana-Farber Cancer Institute, Inc. Stabilized p53 peptides and uses thereof
US8637686B2 (en) 2007-02-23 2014-01-28 Aileron Therapeutics, Inc. Triazole macrocycle systems
US10030049B2 (en) 2007-02-23 2018-07-24 Aileron Therapeutics, Inc. Triazole macrocycle systems
US9023988B2 (en) 2007-02-23 2015-05-05 Aileron Therapeutics, Inc. Triazole macrocycle systems
US9493509B2 (en) 2007-02-23 2016-11-15 Aileron Therapeutics, Inc. Triazole macrocycle systems
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JP2015107966A (ja) * 2007-02-23 2015-06-11 エイルロン セラピューティクス，インコーポレイテッド トリアゾール大環状系
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JP2010519318A (ja) * 2007-02-23 2010-06-03 エイルロン セラピューティクス，インコーポレイテッド トリアゾール大環状系
US9957296B2 (en) 2007-02-23 2018-05-01 Aileron Therapeutics, Inc. Triazole macrocycle systems
US10301351B2 (en) 2007-03-28 2019-05-28 President And Fellows Of Harvard College Stitched polypeptides
US10022422B2 (en) 2009-01-14 2018-07-17 Alleron Therapeutics, Inc. Peptidomimetic macrocycles
US10300109B2 (en) 2009-09-22 2019-05-28 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9957299B2 (en) 2010-08-13 2018-05-01 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9522947B2 (en) 2011-10-18 2016-12-20 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10308699B2 (en) 2011-10-18 2019-06-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US9096684B2 (en) 2011-10-18 2015-08-04 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10213477B2 (en) 2012-02-15 2019-02-26 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10227380B2 (en) 2012-02-15 2019-03-12 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
US9604919B2 (en) 2012-11-01 2017-03-28 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US9845287B2 (en) 2012-11-01 2017-12-19 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10669230B2 (en) 2012-11-01 2020-06-02 Aileron Therapeutics, Inc. Disubstituted amino acids and methods of preparation and use thereof
US10471120B2 (en) 2014-09-24 2019-11-12 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10905739B2 (en) 2014-09-24 2021-02-02 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and formulations thereof
US10253067B2 (en) 2015-03-20 2019-04-09 Aileron Therapeutics, Inc. Peptidomimetic macrocycles and uses thereof
US10059741B2 (en) 2015-07-01 2018-08-28 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
US10023613B2 (en) 2015-09-10 2018-07-17 Aileron Therapeutics, Inc. Peptidomimetic macrocycles as modulators of MCL-1

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