Stitched polypeptides
The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.
1. An amino acid having Formula (A), or a 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 R a 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; or an amino protecting group;
each instance of R c 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 hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
each instance of R e is, independently, —R 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; a hydroxyl protecting group;
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; an amino protecting group; or 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; or substituted or unsubstituted heteroarylene;
or R f and R a together form a substituted or unsubstituted heterocyclic or heteroaromatic ring;
each instance of x is, independently, an integer between 0 to 3; and
is a double or triple bond.
2. The amino acid of claim 1 , wherein R a is alkyl.
3. The amino acid of claim 1 , wherein R a is hydrogen.
4. The amino acid of claim 1 , wherein R a is —COCH 3 .
5. The amino acid of claim 1 , wherein R f is hydrogen.
6. The amino acid of claim 1 , wherein R e is hydrogen.
7. The amino acid of claim 1 , wherein R f is an amino protecting group.
8. The amino acid of claim 7 , wherein R f is Boc.
9. The amino acid of claim 7 , wherein R f is Fmoc.
10. The amino acid of claim 1 , wherein each is a double bond.
11. The amino acid of claim 1 of Formula (A-2):
12. The amino acid of claim 11 of one of the following formulae:
13. A method of preparing an alphahelical polypeptide, said method comprising the steps of:
(i) providing an amino acid of Formula (A):
(ii) providing an amino acid of the Formula (B):
each instance of L 1 and L 2 is, independently, a straight chain alkylene of 3 to 7 carbon atoms;
each instance of R a 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; or an amino protecting group;
each instance of R c 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 hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; cyano; isocyano; halo; or nitro;
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; or a hydroxyl protecting group;
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; an amino protecting group; or 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; or substituted or unsubstituted heteroarylene;
or R f and R a together form a substituted or unsubstituted heterocyclic or heteroaromatic ring;
each instance of x is, independently, an integer between 0 to 3;
is a double or triple bond;
K is a straight chain alkylene of 1 to 7 carbon atoms; and
R b is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;
(iii) providing an amino acid of the Formula (C):
and
is a double or triple bond;
M is a straight chain alkylene of 1 to 7 carbon atoms;
R b is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;
(iv) providing at least one additional amino acid;
(v) coupling said amino acids of Formulae (A), (B), and (C) with at least one amino acid of step (iv); and
(vi) treating the polypeptide of step (v) with a catalyst.
14. The method of claim 13 , wherein said catalyst is a ring closing metathesis catalyst.
15. The method of claim 13 , wherein said catalyst is a ruthenium catalyst.
16. The method of claim 13 , wherein each R a is hydrogen or methyl.
17. The method of claim 13 , wherein each R a is hydrogen.
18. The method of claim 13 , wherein at least one R a is —COCH 3 .
19. The method of claim 13 , wherein each R b is alkyl.
20. The method of claim 13 , wherein each R b is methyl.
21. The method of claim 13 , wherein each R f is hydrogen.
22. The method of claim 13 , wherein each R e is hydrogen.
23. The method of claim 13 , wherein each R f is an amino protecting group.
24. The method of claim 13 , wherein each R f is Boc.
25. The method of claim 13 , wherein each R f is Fmoc.
26. The method of claim 13 , wherein each is a double bond.
27. The method of claim 13 , wherein the amino acid of Formula (A) is an amino acid of Formula (A-2):
28. The method of claim 27 , wherein the amino acid of Formula (A-2) is of one of the following formulae:
29. The amino acid of claim 1 , wherein both correspond to a double bond.
30. The amino acid of claim 1 , wherein both correspond to a triple bond.
31. The amino acid of claim 1 , wherein R c is hydrogen.
32. The amino acid of claim 1 , wherein L 1 and L 2 are both —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —.