Heterogeneous foldamers containing α, β, and/or γ-amino acids

1. An isolated, unnatural polypeptide compound comprising six or more residues, wherein each residue is independently selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues;

wherein at least two of the residues are one each of a β-amino acid residue and a γ-amino acid residue, wherein one of the β-amino acid residue or the γ-amino acid residue is cyclically-constrained in a monocyclic or bicyclic C 4 to C 10 cycloalkyl ring;

wherein at least one of the residues is an α-amino acid residue, and the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof; and

wherein the polypeptide comprises an N-terminus.

2. The compound of claim 1 , wherein the N-terminus comprises an N-terminal residue, the N-terminal residue is one of the six or more residues, and the N-terminal residue comprises a free amino group, a protonated amino group, or an amino group protected with an amino-terminus protecting group.

3. The compound of claim 2 , wherein the amino-terminus protecting group is selected from the group consisting of methyl, formyl, ethyl, acetyl, t-butyl, benzyl, trifluoroacetyl, t-butoxycarbonyl, benzoyl, 4-methylbenzyl, benzyloxymethyl, 4-nitrophenyl, benzyloxycarbonyl, 2-nitrobenzoyl, 2-nitrophenylsulphenyl, 4-toluenesulphonyl, pentafluorophenyl, diphenylmethyl, 2-chlorobenzyloxycarbonyl, 2,4,5-trichlorophenyl, 2-bromobenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, triphenylmethyl, and 2,2,5,7,8-pentamethyl-chroman-6- sulphonyl.

4. The compound of claim 1 , wherein one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof.

5. An isolated, unnatural polypeptide compound comprising six or more residues, wherein each residue is independently selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues;

wherein at least two of the residues are one each of a β-amino acid residue and a γ-amino acid residue, wherein one of the β-amino acid residue or the γ-amino acid residue is cyclically-constrained in a monocyclic or bicyclic C 4 to C 10 cycloalkyl ring; and

wherein at least one of the residues is an α-amino acid residue, and the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof;

wherein one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof and N-alkylated derivatives thereof.

6. An isolated, unnatural polypeptide compound selected from the group consisting of:

wherein:

each X and each Z is independently variable and is selected from the group consisting of α-amino acid residues, β-amino acid residues, and γ-amino acid residues, provided that at least one X or Z comprises an α-amino acid residue and at least another two of X or Z comprise two cyclically-constrained γ-amino acid residues;

the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof, and N-alkylated derivatives thereof;

one or more of the at least one α-amino acid residue is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, nor-valine, nor-leucine, ornithine, hydroxylated derivatives thereof, and N-alkylated derivatives thereof;

each cyclically-constrained γ-amino acid residue is independently selected from the group consisting of:

R, together with the carbons to which it is attached, and further together with the β-position carbon in the γ-amino acid backbone where appropriate, independently defines a substituted or unsubstituted, monocyclic or bicyclic C 4 to C 10 cycloalkyl or cycloalkenyl moiety, provided that, in at least one of the cyclically-constrained γ-amino acid residues, R, together with the carbons to which it is attached, and further together with the β-position carbon in the γ-amino acid backbone where appropriate, defines a substituted or unsubstituted, monocyclic or bicyclic C 4 to C 10 cycloalkyl moiety;

each “Y” is independently variable and is a single bond or a reverse-turn moiety;

“A” is independently selected from the group consisting of hydrogen and an amino-terminus protecting group, and “A′” is selected from the group consisting of hydroxyl and a carboxy-terminus protecting group; and

each “a,” “c,” and “d” is an independently variable positive integer; and

“a”+“c”>3; and

salts thereof.

7. The compound of claim 6 , wherein at least one R, together with the carbons to which it is attached and together with a β-position carbon in the γ-amino acid backbone when the β-position carbon is present, independently defines a substituted C 5 to C 6 cycloalkyl or cycloalkenyl moiety; and

substituents on the cycloalkyl or cycloalkenyl moieties are independently selected from the group consisting of linear, branched, or cyclic C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 —OR 2 , —(CH 2 ) n+1 —SR 2 , —(CH 2 ) n+1 —S(═O)—CH 2 —R 2 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 2 , —(CH 2 ) n+1 —NR 2 R 2 , —(CH 2 ) n+1 —NHC(═O)R 2 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 2 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —S—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 1 2 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 1 , —(CH 2 ) n+1 —N—{(CH 2 ) m —R 1 } 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 1 , —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n —OR, —(CH 2 ) n —SR 2 , —(CH 2 ) n —S(═O)—CH 2 —R 2 , —(CH 2 ) n —S(═O) 2 —CH 2 —R 2 , —(CH 2 ) n —NR 2 R 2 , —(CH 2 ) n —NHC(═O)R 2 , —(CH 2 ) n —NHS(═O) 2 —CH 2 —R 2 , —(CH 2 ) n —O—(CH 2 ) m —R 1 , —(CH 2 ) n —S—(CH 2 ) m —R 1 , —(CH 2 ) n —S(═O)—(CH 2 ) m —R 1 , —(CH 2 ) n —S(═O) 2 —(CH 2 ) m —R 1 , —(CH 2 ) n NH—(CH 2 ) m —R 1 , —(CH 2 ) n —N—{(CH 2 ) m —R 1 } 2 , —(CH 2 ) n —NHC(═O)—(CH 2 ) m —R 1 , and —(CH 2 ) n —NHS(═O) 2 —(CH 2 ) m —R 1 ;

wherein m is an integer of from 2-6 and n is an integer of from 0-6;

wherein R 2 is independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and

wherein R 1 is selected from the group consisting of hydroxy, C 1 -C 6 -alkyloxy, aryloxy, heteroaryloxy, thio, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C 1 -C 6 -alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C 1 -C 6 -alkylamino, carboxylic acid, carboxamide, mono- or di-C 1 -C 6 -alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, C 1 -C 6 -alkyl ester, aryl ester, heteroaryl ester, sulfonic acid, sulfonamide, mono- or di-C 1 -C 6 -alkyl sulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane.

8. The compound of claim 6 , wherein at least one Y is a reverse turn moiety independently selected from the group consisting of a prolyl-glycolic acid residue, a di-nipecotic acid residue, or a compound of the following formula:

where each R 3 is independently variable and is selected from the group consisting of hydrogen, linear, branched, or cyclic C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl, and mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and

where each R 4 is independently selected from the group consisting of hydrogen, hydroxy, linear, branched, or cyclic C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 - alkyl; mono- or bicyclic heteroaryl-C 1 -C 6 - alkyl; C 1 -C 6 -alkyloxy, aryloxy, heteroaryloxy, thio, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C 1 -C 6 -alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C 1 -C 6 -alkylamino, carboxylic acid, carboxamide, mono- or di-C 1 -C 6 -alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C 1 -C 6 -alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane.

9. A method of probing, disrupting, or mimicking binding interactions between two protein molecules or fragments thereof, the method comprising:

in an in vivo, in vitro, or ex vivo reaction between the two proteins,

(a) introducing to the reaction an unnatural polypeptide compound according to claim 1 ; and then

(b) quantifying any effect of the added compound from step (a) on thermodynamic or kinetic parameters of the binding interaction between the two protein molecules or fragments thereof.