Investigating the stereochemistry of binding to HIV-1 protease with inhibitors containing isomers of 4-amino-3-hydroxy-5-phenylpentanoic acid.
A series of inhibitors containing all possible isomers of 4-amino-3-hydroxy-5-phenylpentanoic acid was synthesized and tested for inhibition of HIV-1 protease. Incorporation of the (3S,4S) isomer of the t-butyloxycarbonyl protected amino acid into the sequence Glu-Phe resulted in a potent inhibitor of HIV-1 protease (Ki = 63 nM). This inhibitor is at least 47-times more potent than the inhibitors containing other isomers of 4-amino-3-hydroxy-5-phenylpentanoic acid, indicating that the (3S,4S) isomer is the preferred isomer for binding to HIV-1 protease.
Rational Drug Design, Boston University Medical Center, MA 02118.
B
B
Raju
M S
MS
Deshpande
D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors; D016333:HIV Protease / Q000737:chemistry*; D007700:Kinetics; D008969:Molecular Sequence Data; D013237:Stereoisomerism; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D016333:HIV Protease