Polymer-based compositions and conjugates of HIV entry inhibitors
View Patent ↗Provided herein are water-soluble polymer conjugates and polymer-based compositions of HIV entry inhibitors. Also provided are methods for synthesizing and administering such conjugates and compositions.
1. An HIV-entry inhibitor-water-soluble polymer conjugate having a structure:
wherein:
EI is an HIV-entry inhibitor that corresponds to T-20 or T-1249,
POLY is a water-soluble, poly(alkylene oxide),
k is selected from 1, 2, and 3,
L is —O— or —NH—C(O)—,
Ar is an aromatic group,
—NH-EI in structure II represents an amino group of the EI,
P is a spacer,
Z is —O— or —NH—,
—O-EI in structure III represents a hydroxyl group of the EI,
and further wherein the poly(alkylene oxide) is covalently attached to the entry inhibitor by a hydrolyzable linkage effective to release the entry inhibitor upon hydrolysis.
2. The conjugate of claim 1 , wherein each poly(alkylene oxide) is a poly(ethylene glycol).
3. The conjugate of claim 2 , wherein each poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy.
4. The conjugate of claim 3 , wherein each poly(ethylene glycol) is terminally capped with methoxy.
5. The conjugate of claim 2 , wherein each poly(ethylene glycol) has a molecular weight in a range from about 2,000 Daltons to about 85,000 Daltons.
6. The conjugate of claim 1 , wherein each POLY possesses an architecture selected from the group consisting of linear, branched, and forked.
7. The conjugate of claim 1 , wherein the EI is T-20.
8. The conjugate of claim 1 , wherein the EI is T-1249.
9. The conjugate of claim 7 , having structure II, wherein the T-20 is modified by hydrolyzable covalent attachment of the poly(alkylene oxide) at one or both of Lys-18, and Lys28.
10. The conjugate of claim 9 , wherein the T-20 is further additionally modified by hydrolyzable covalent attachment of the poly(alkylene oxide) at the N-terminus.
11. The conjugate of claim 8 , having structure II, wherein the T-1249 is modified by hydrolyzable covalent attachment of the poly(alklene oxide) at from one to three of amino acid positions selected from Lys7, Lys21, Lys28 and Lys31.
12. The conjugate of claim 1 , where in structure III, P, when taken together with —NH—P—Z—C(O)—, is a residue of a naturally or non-naturally occurring amino acid.
13. The conjugate of claim 1 , where Ar in structure II is an ortho, meta, or para-substituted phenyl group.
14. The conjugate of claim 1 having structure III, wherein P, when taken together with —NH—P—Z—C(O)—, is glyine or alanine.
15. The conjugate of claim 13 , having structure:
where n ranges from 2 to about 3400.
16. The conjugate of claim 1 , wherein k equals 1.
17. A composition comprising a plurality of conjugates of claim 1 , each conjugate comprised within the plurality having structure II and having a value of k from 1-3.
18. A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable excipient.
19. A method for making an HIV-entry inhibitor water-soluble polymer conjugate having structure H of claim 1 , comprising contacting, under suitable conjugation conditions, an HIV entry inhibitor that is either T-20 or T-1249, with a polymeric reagent having the structure:
where POLY and Ar are as defined in claim 1 , and where FG is a functional group capable of reaction with an amino group of the HIV entry inhibitor to form a hydrolyzable carbamate linkage.
20. A composition comprising a plurality of mono-conjugates of claim 1 , each conjugate comprised within the plurality having structure II, and having the same chemical structure, where the value of k for each conjugate is 1, and the composition comprises at least two different positional isomers.
21. A composition comprising a plurality of conjugates of claim 1 , each conjugate comprised within the plurality having structure III and having a value of k from 1-3.
22. A composition comprising a plurality of mono-conjugates of claim 1 , each conjugate comprised within the plurality having structure III and having the same chemical structure, where the value of k for each conjugate is 1, and the composition comprises at least two different positional isomers.