Stitched polypeptides

1. A substantially alpha-helical polypeptide of the formula:

or a pharmaceutically acceptable salt thereof;

wherein:

each instance of K, L 1 , L 2 , and M is, independently, a cyclic or acyclic, branched or unbranched, substituted or unsubstituted C 1-8 alkylene;

each instance of R a is, independently, hydrogen; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; a substituted or unsubstituted heteroaryl; a cyclic or acyclic, substituted or unsubstituted acyl; or R a is a suitable amino protecting group;

each instance of R b is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;

each instance of R e is, independently, —R E , —OR E , —N(R E ) 2 , or —SR E , wherein each instance of R E is, independently, hydrogen; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; a substituted or unsubstituted heteroaryl; a substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino, or thiol protecting group; or two R E groups together form a 5- to 6-membered heterocyclic or heteroaromatic ring;

each instance of R f is, independently, hydrogen; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; a substituted or unsubstituted heteroaryl; a substituted or unsubstituted acyl; a resin; a suitable amino protecting group; a label optionally joined by a linker, wherein the linker is selected from cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkynylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; or substituted or unsubstituted acylene; or R f and R a together form a 5- to 6-membered heterocyclic or heteroaromatic ring;

each instance of R KL , R LL , and R LM , is, independently, hydrogen; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; azido; cyano; isocyano; halo; or nitro;

each instance of X AA is, independently, an alpha-amino acid;

each instance of y and z is, independently, an integer from 2 to 6;

each instance of j is, independently, an integer from 1 to 10;

each instance of p is, independently, an integer from 0 to 10;

each instance of s and t is, independently, an integer from 0 and 100;

each instance of u, v, and q, is independently, an integer from 0 to 4; and

corresponds to a single, double, or triple bond.

2. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein all correspond to a single or double bond.

3. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein all correspond to a single bond.

4. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein all correspond to a double bond.

5. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein R a is hydrogen.

6. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein R b is hydrogen.

7. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , wherein R f is a label optionally joined by a linker.

8. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 7 , wherein R f is a label joined by a heteroalkylene linker.

9. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 8 , wherein the heteroalkylene linker is selected from the group consisting of:

10. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 8 , wherein the label is selected from the group consisting of:

11. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1 , that is selected from the group consisting of SEQ ID NOs: 1-122.

12. A method of making the alpha-helical polypeptide of claim 1 or its pharmaceutically acceptable salt, comprising:

coupling amino acids of formulae (A), (B), and (C):

or salts of one of more of these amino acids, with at least one further amino acid or a salt thereof, to form a precursor polypeptide or its salt; and

treating the precursor polypeptide or its salt with a catalyst to form the polypeptide or its pharmaceutically acceptable salt;

wherein in the amino acids (A) (B) and (C):

each instance of x is, independently, an integer from 0 to 3;

each instance of R c is, independently, hydrogen; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; a cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; a substituted or unsubstituted aryl; a substituted or unsubstituted heteroaryl; a cyclic or acyclic, substituted or unsubstituted acyl; a substituted or unsubstituted hydroxyl; a substituted or unsubstituted thiol; a substituted or unsubstituted amino; cyano; isocyano; halo; or nitro; and

each instance of independently corresponds to a double or triple bond.

13. The method of claim 12 , wherein the catalyst is a ring closing metathesis catalyst.

14. The method of claim 12 , wherein the catalyst is a ruthenium catalyst.

15. A pharmaceutical composition comprising at least one of the substantially alpha-helical polypeptide of claim 1 , or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

16. The substantially alpha-helical polypeptide of claim 1 , or its pharmaceutically acceptable salt, wherein y is 3, and z is 3.

17. The substantially alpha-helical polypeptide of claim 1 , or its pharmaceutically acceptable salt, wherein y is 3, and z is 6.

18. The alpha-helical polypeptide of claim 1 , or its pharmaceutically acceptable salt, wherein y is 6, and z is 3.

19. An alpha-helical polypeptide of the formula:

or a pharmaceutically acceptable salt thereof;

wherein:

each instance of L 1 and L 2 is independently a straight chain alkylene of 3 to 7 carbon atoms;

each instance of K and M is independently, a straight chain alkylene of 1 to 7 carbon atoms;

each instance of R a is hydrogen or alkyl of 1 to 6 carbon atoms or acyl;

each instance of R b is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;

each instance of R e is, independently, —R E , —OR E , —N(R E ) 2 or —SR E , wherein each instance of R E is, independently, hydrogen, cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino, or thiol protecting group; or two R E groups together form a substituted or unsubstituted 5- to 6-membered heterocyclic or heteroaromatic ring;

each instance of R f is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; a resin; a suitable amino protecting group; a label optionally joined by a linker, wherein the linker is selected from cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted alkynylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkenylene; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroalkynylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; or substituted or unsubstituted acylene; or R f and R a together form a substituted or unsubstituted 5- to 6-membered heterocyclic or heteroaromatic ring;

each instance of X AA is, independently, an alpha-amino acid;

each instance of y and z is, independently, an integer from 2 to 6;

j is, an integer between 1 to 10;

each instance of p is, independently, an integer between 0 to 10 inclusive;

R KL , R LL and R LM are independently hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted acyl; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; azido; cyano; isocyano; halo; or nitro;

each instance of s and t is, independently, an integer from 0 to 100;

u, v, and q, are independently an integer from 0 to 4;

corresponds to a single, double or triple bond.

20. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein R a is hydrogen.

21. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein R b is hydrogen or methyl.

22. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein y is 2, and z is 2, 3, 5 or 6.

23. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein y is 3, and z is 2, 3, 5 or 6.

24. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein y is 5, and z is 2, 3, 5 or 6.

25. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein y is 6, and z is 2, 3, 5 or 6.

26. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein corresponds to a double bond.

27. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein L 1 and L 2 are both CH 2 CH 2 CH 2 .

28. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein L 1 and L 2 are both CH 2 CH 2 CH 2 CH 2 .

29. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein L 1 and L 2 are both CH 2 CH 2 CH 2 CH 2 CH 2 .

30. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein L 1 and L 2 are both CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 .

31. The polypeptide or its pharmaceutically acceptable salt of claim 19 , wherein L 1 and L 2 are both CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 .

32. The polypeptide or its pharmaceutically acceptable salt of claim 19 , selected from the group consisting of SEQ ID NO: 10 to SEQ ID No: 20, SEQ ID NO: 25, SEQ ID NO: 27 to 35, SEQ ID NO: 37 to SEQ ID NO: 122, and pharmaceutically acceptable salts thereof.

33. A pharmaceutical composition comprising the polypeptide or its pharmaceutically acceptable salt of claim 19 and a pharmaceutically acceptable carrier.