Non-Imuunosuppressive cyclosporins and their use in the prevention and treatment of HIV infection
AssigneeWisconsin Alumni Research Foundation
InventorsDaniel H. Rich, Michael E. Solomon
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Abstract
Disclosed are cyclosporin analogs having amino acid residue substitutions at positions 1, 3, or 7 of the cyclosporin peptide backbone. Also disclosed are conjugates of these cyclosporin analogs in which an HIV protease inhibitor moiety is conjugated to the position-7 amino acid residue of the cyclosporin. These compounds simultaneously bind to and inhibit cyclophilin and HIV protease. The compounds have good bioavailability and potent HIV inhibitory activity. They are useful in the treatment and prevention of HIV-mediated disorders, including AIDS.
Claims31
Non-immunosupressive cyclosporins comprising a cyclic undecapeptide of Formula I:
- wherein V is a MeLeu(3-OH), MeLeu, MeSer, MeSer-PG, MeThr, or MeThr-PG residue;
- W is a (D)-N-methyl-amino acid or an N-methylglycyl residue;
- X and X′ are independently an N-methyl-leucinyl or an N-methylalanyl residue;
- Y is a lysyl, homo-lysyl, ornithinyl, lysyl-PG, homo-lysyl-PG, or ornithinyl-PG residue;
- wherein each PG is, independently, a side-chain protecting group;
- and
- Z is absent or is an HIV protease inhibitor moiety conjugated to Y via a side-chain on Y and selected from the group consisting of
- wherein R is Ac-Ser-Leu-Asn;
- and salts thereof.
A compound comprising a conjugate produced by:
- (a) forming a cyclosporin analog of formula
- wherein V is a MeLeu(3-OH), MeLeu, MeSer, MeSer-PG, MeThr, or MeThr-PG residue, wherein each PG is, independently, a side-chain protecting group;
- W is a (D)-N-methyl-amino acid residue or an N-methylglycyl residue;
- X and X′ are independently an N-methyl-leucinyl or an N-methylalanyl residue;
- and Y is a lysyl, is formed;
- and comprising a lysyl residue having an ε-aminobutyl side-chain at position-7 of the cyclosporin analog;
- and
- (b) conjugating an HIV protease inhibitor, Z, to the ε-aminobutyl side-chain of the lysyl residue, Z being selected from the group consisting of
- wherein R is Ac-Ser-Leu-Asn;
- and wherein the compound simultaneously binds to and inhibits the action of cyclophilin and HIV protease.
Dependencies are inferred from the claim text.