초록

The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of viral disease.

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1. A peptidomimetic macrocycle or a pharmaceutically-acceptable salt thereof, wherein the peptidomimetic macrocycle: (i) comprises two non-natural amino acids connected by a macrocycle-forming linker; (ii) has an amino acid sequence Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12

1. A peptidomimetic macrocycle or a pharmaceutically-acceptable salt thereof, wherein the peptidomimetic macrocycle: (i) comprises two non-natural amino acids connected by a macrocycle-forming linker; (ii) has an amino acid sequence Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18; and (iii) has at least about 60% sequence identity to a sequence of Table 1b; wherein Xaa0 is —H or an N-terminal capping group;each Xaa1-Xaa10 and Xaa12-Xaa15 is independently an amino acid;Xaa11 is Ala;each Xaa16 and Xaa17 is independently absent or an amino acid; andXaa18 is —NH2, —OH, or a C-terminal capping group. 2. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the macrocycle-forming linker connects amino acids Xaa5 and Xaa9. 3. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the macrocycle-forming linker connects amino acids Xaa5 and Xaa12. 4. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (Ia): wherein: each of Xaa6, Xaa7, Xaa8, Xaa10, Xaa11, Xaa12, and Xaa13 is independently an amino acid, wherein at least three, four, five, or each of Xaa6, Xaa7, Xaa8, Xaa10, Xaa11, and Xaa12, are the same amino acid as the amino acid at the corresponding position of the sequence X5-Thr6-Leu7-Leu8-X9-Leu10-Ala11-Val12/Ala12, where each of X5 and X9 is independently an amino acid (SEQ ID NO: 1);each D and E is independently an amino acid;each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the α position of one of said D or E amino acids;each L and L′ is independently a macrocycle-forming linker;each R3 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v is independently is 4;each w is independently 2, 3, or 4; andu is 1. 5. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (Ib): wherein: each of Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11 and Xaa13 is independently an amino acid, wherein at least three, four, five, or each of Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, and Xaa11 are the same amino acid as the amino acid at the corresponding position of the sequence X5-Thr6-Leu7-Leu8-Phe9-Leu10-Ala11-X12, where each of X5 and X12 is independently an amino acid (SEQ ID NO: 2);each D and E is independently an amino acid;each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the α position of one of said D or E amino acids;each L and L′ is independently a macrocycle-forming linker;each R3 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v is 4;each w is 2, 3, or 4; andu is 1. 6. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle is a compound of Formula (I): wherein: each A, B, C, D, and E is independently an amino acid;each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R1 and R2 forms a macrocycle-forming linker L′ connected to the α position of one of said D or E amino acids;each L and L′ is independently a macrocycle-forming linker;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;each v and w is independently an integer from 0-1000;u is an integer from 1-10; andeach x, y and z is independently an integer from 0-10. 7. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 8. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein each amino acid connected by the macrocycle-forming linker is an α,α-disubstituted amino acid. 9. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein u is 1. 10. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein x+y+z is 2, 3, 5 or 6. 11. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each v is independently an integer from 0-10. 12. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each v is 4. 13. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein [D]v is -Asn4-Val3-Glu2-Nle1 (SEQ ID NO: 4). 14. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein [D]v is -Asn4-Val3-Glu2-Phe1 (SEQ ID NO: 5). 15. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each w is independently an integer from 0-10. 16. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each w is 1, 2, 3, 4, 5, 6, or 8. 17. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each of the first two amino acids represented by E comprises an uncharged side chain or a negatively charged side chain. 18. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein the first, second, third or fourth amino acid represented by E comprises a hydrophobic side chain. 19. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 18, wherein the hydrophobic side chain is a small hydrophobic side chain. 20. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each E is independently an amino acid selected from the group consisting of Ala, D-Ala, Aib, Lys, Leu, Ser, Glu, and Gln. 21. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each L is independently alkylene, alkenylene, or alkynylene. 22. The peptidomimetic macrocycle of claim 6, wherein each R1 and R2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo. 23. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each R1 and R2 is independently alkyl. 24. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 6, wherein each L and L′ independently has a formula -L1-L2-, wherein each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [—R4—K—R4-]n, each being optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2 or CONR3; andeach n is independently an integer from 1-5. 25. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 24, wherein each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R5. 26. The peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 24, wherein each L1 and L2 is independently alkylene, alkenylene or alkynylene. 27. The peptidomimetic macrocycle of claim 24, wherein each L1 and L2 is independently alkylene or alkenylene. 28. A pharmaceutical composition comprising the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1 and a pharmaceutically acceptable excipient. 29. A method of treating influenza infection in a subject comprising administering to the subject the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle has at least about 90% sequence identity to a sequence of Table 1b. 30. The method of claim 29, wherein the administering comprises administering subcutaneously or parenterally. 31. The method of claim 29, wherein the administering comprises administering a single dose of the peptidomimetic macrocycle. 32. A method of inhibiting the activity of the RNA-dependent RNA polymerase of an influenza virus in a subject comprising administering to the subject the peptidomimetic macrocycle or the pharmaceutically-acceptable salt of claim 1, wherein the peptidomimetic macrocycle has at least about 90% sequence identity to a sequence of Table 1 b.