The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.
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1. An amino acid having Formula (A), or a salt thereof: wherein: each instance of L1 and L2 is, independently, a straight chain alkylene of 3 to 7 carbon atoms;each instance of Ra is, independently, hydrogen; cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic; cyclic
1. An amino acid having Formula (A), or a salt thereof: wherein: each instance of L1 and L2 is, independently, a straight chain alkylene of 3 to 7 carbon atoms;each instance of Ra 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 Rc 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 Re is, independently, —RE, wherein each instance of —RE 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 Rf 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 Rf and Ra 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 Ra is alkyl. 3. The amino acid of claim 1, wherein Ra is hydrogen. 4. The amino acid of claim 1, wherein Ra is —COCH3. 5. The amino acid of claim 1, wherein Rf is hydrogen. 6. The amino acid of claim 1, wherein Re is hydrogen. 7. The amino acid of claim 1, wherein Rf is an amino protecting group. 8. The amino acid of claim 7, wherein Rf is Boc. 9. The amino acid of claim 7, wherein Rf 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 L1 and L2 is, independently, a straight chain alkylene of 3 to 7 carbon atoms;each instance of Ra 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 Rc 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 Re 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 Rf 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 Rf and Ra 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; andRb 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;Rb 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 Ra is hydrogen or methyl. 17. The method of claim 13, wherein each Ra is hydrogen. 18. The method of claim 13, wherein at least one Ra is —COCH3. 19. The method of claim 13, wherein each Rb is alkyl. 20. The method of claim 13, wherein each Rb is methyl. 21. The method of claim 13, wherein each Rf is hydrogen. 22. The method of claim 13, wherein each Re is hydrogen. 23. The method of claim 13, wherein each Rf is an amino protecting group. 24. The method of claim 13, wherein each Rf is Boc. 25. The method of claim 13, wherein each Rf 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 Rc is hydrogen. 32. The amino acid of claim 1, wherein L1 and L2 are both —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, or —CH2CH2CH2CH2CH2CH2—.
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