Substrate analog inhibitors of HIV-1 protease containing phenylnorstatine as a transition state element.
Substrates of HIV-1 protease are classified into three groups (A, B and C) based on the amino acid residues present at P1' and P2' sites. Replacement of the scissile amide bond by phenylnorstatine in representative substrate analog sequences from class A, B and C, yielded inhibitors of HIV-1 protease. Of the twelve inhibitors synthesized in this series, class C substrate analog inhibitors are more potent inhibitors (Ki's 3.3-24 microM) than either class A or class B inhibitors. In this series of inhibitors, the (2S,3S) isomer of phenylnorstatine is preferred over the other isomers as a "transition state element" for design of inhibitors of 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; D017320:HIV Protease Inhibitors; D008969:Molecular Sequence Data; D010654:Phenylbutyrates / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid