The present invention provides inventive stitched polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stitched polypeptides.
대표청구항▼
1. A substantially alpha-helical polypeptide of the formula: or a pharmaceutically acceptable salt thereof;wherein: each instance of K, L1, L2, and M is, independently, a cyclic or acyclic, branched or unbranched, substituted or unsubstituted C1-8 alkylene;each instance of Ra is, independently, hydr
1. A substantially alpha-helical polypeptide of the formula: or a pharmaceutically acceptable salt thereof;wherein: each instance of K, L1, L2, and M is, independently, a cyclic or acyclic, branched or unbranched, substituted or unsubstituted C1-8 alkylene;each instance of Ra 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 Ra is a suitable amino protecting group;each instance of Rb is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;each instance of Re is, independently, —RE, —ORE, —N(RE)2, or —SRE, wherein each instance of RE 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 RE groups together form a 5- to 6-membered heterocyclic or heteroaromatic ring;each instance of Rf 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 Rf and Ra together form a 5- to 6-membered heterocyclic or heteroaromatic ring;each instance of RKL, RLL, and RLM, 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 XAA 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 Ra is hydrogen. 6. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein Rb is hydrogen. 7. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 1, wherein Rf is a label optionally joined by a linker. 8. The substantially alpha-helical polypeptide or its pharmaceutically acceptable salt of claim 7, wherein Rf 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 Rc 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; andeach 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 L1 and L2 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 Ra is hydrogen or alkyl of 1 to 6 carbon atoms or acyl;each instance of Rb is hydrogen or cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;each instance of Re is, independently, —RE, —ORE, —N(RE)2or —SRE, 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; substituted or unsubstituted acyl; a resin; a suitable hydroxyl, amino, or thiol protecting group; or two RE groups together form a substituted or unsubstituted 5- to 6-membered heterocyclic or heteroaromatic ring;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; 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 Rf and Ra together form a substituted or unsubstituted 5- to 6-membered heterocyclic or heteroaromatic ring;each instance of XAA 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;RKL, RLL and RLM 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 Ra is hydrogen. 21. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein Rb 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 L1 and L2 are both CH2CH2CH2. 28. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L1 and L2 are both CH2CH2CH2CH2. 29. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L1 and L2 are both CH2CH2CH2CH2CH2. 30. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L1 and L2 are both CH2CH2CH2CH2CH2CH2. 31. The polypeptide or its pharmaceutically acceptable salt of claim 19, wherein L1 and L2 are both CH2CH2CH2CH2CH2CH2CH2. 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.
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