Compositions and methods for the treatment of viral infections
Compositions and methods for the treatment of viral infections include conjugates containing inhibitors of viral neuraminidase (e.g., zanamivir, peramivir, or analogs thereof) linked to an Fc monomer, an Fc domain, and Fc-binding peptide, an albumin protein, or albumin-binding peptide. In particular, conjugates can be used in the treatment of viral infections (e.g., influenza viral infections).
1. A conjugate described by formula (D-II-6):
wherein each E comprises an Fc domain monomer;
n is 1 or 2;
T is an integer from 1 to 20;
L is a linker;
R 7 is selected from C1-C20 alkyl; and
the squiggly line indicates that L is covalently attached to E;
or a pharmaceutically acceptable salt thereof.
2. The conjugate of claim 1 , wherein the squiggly line indicates that L is covalently attached to a nitrogen atom of a solvent-exposed lysine of E.
3. The conjugate of claim 1 , wherein the squiggly line indicates that L is covalently attached to a sulfur atom of a solvent-exposed cysteine of E.
4. The conjugate of claim 1 , wherein n is 2, and the two Es dimerize with each other to form an Fc domain.
5. The conjugate of claim 1 , wherein T is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
6. A population of conjugates of claim 1 , wherein the average value of T is 1 to 10.
7. The conjugate of claim 1 , wherein R 7 is methyl, ethyl, propyl, or butyl.
8. The conjugate of claim 7 , wherein the conjugate is described by formula (D-II-7):
or a pharmaceutically acceptable salt thereof.
9. The conjugate of claim 8 , wherein the conjugate is described by formula (D-II-8):
wherein L′ is the remainder of L, and
y 1 and y 2 are each independently an integer from 1-20,
or a pharmaceutically acceptable salt thereof.
10. The conjugate of claim 9 , wherein the conjugate has the structure of:
or a pharmaceutically acceptable salt thereof.
11. The conjugate of claim 10 , wherein the conjugate has the structure of:
or a pharmaceutically acceptable salt thereof.
12. The conjugate of claim 11 , wherein n is 2, and the two Es dimerize with each other to form an Fc domain.
13. The conjugate of claim 11 , wherein T is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
14. A population of conjugates of claim 11 , wherein the average value of T is 1 to 10.
15. The conjugate of claim 1 , wherein each E comprises an amino acid sequence independently selected from of any one of SEQ ID NOs: 1-138.
16. The conjugate of claim 1 , wherein each E comprises an amino acid sequence independently selected from any one of SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, and SEQ ID NO: 77.
17. The conjugate of claim 16 , wherein each E comprises an amino acid sequence of SEQ ID NO: 72.
18. The conjugate of claim 16 , wherein each E comprises an amino acid sequence of SEQ ID NO: 73.
19. The conjugate of claim 16 , wherein each E comprises an amino acid sequence of SEQ ID NO: 76.
20. The conjugate of claim 16 , wherein each E comprises an amino acid sequence of SEQ ID NO: 77.
21. A conjugate described by the structure:
wherein J is an Fc domain comprising two Fc domain monomers,
T is an integer from 1 to 20,
L is a linker;
R 7 is selected from C1-C20 alkyl; and
the squiggly line indicates that L is covalently attached to J;
or a pharmaceutically acceptable salt thereof.
22. The conjugate of claim 21 , wherein the squiggly line indicates that L is covalently attached to a nitrogen atom of a solvent-exposed lysine of J.
23. The conjugate of claim 21 , wherein the squiggly line indicates that L is covalently attached to a sulfur atom of a solvent-exposed cysteine of J.
24. The conjugate of claim 21 , wherein R 7 is methyl, ethyl, propyl, or butyl.
25. The conjugate of claim 21 , wherein T is an integer from 1 to 10.
26. The conjugate of claim 21 , wherein the conjugate has the structure of:
or a pharmaceutically acceptable salt thereof.
27. The conjugate of claim 26 , wherein the conjugate has the structure of:
or a pharmaceutically acceptable salt thereof.
28. The conjugate of claim 27 , wherein each Fc domain monomer comprises an amino acid sequence independently selected from any one of SEQ ID NOs: 1-138.
29. The conjugate of claim 28 , wherein each Fc domain monomer comprises an amino acid sequence independently selected from any one of SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, and SEQ ID NO: 77.
30. The conjugate of claim 29 , wherein each Fc domain monomer comprises an amino acid sequence of SEQ ID NO: 72.
31. The conjugate of claim 29 , wherein each Fc domain monomer comprises an amino acid sequence of SEQ ID NO: 73.
32. The conjugate of claim 29 , wherein each Fc domain monomer comprises an amino acid sequence of SEQ ID NO: 76.
33. The conjugate of claim 29 , wherein each Fc domain monomer comprises an amino acid sequence of SEQ ID NO: 77.
34. The conjugate of 27 , wherein T is an integer from 1 to 10.
35. A population of conjugates of claim 27 , wherein the average value of T is 1 to 10.