James E. Strickler

Peptide substrates and inhibitors of the HIV-1 protease

Oligopeptides containing the consensus retroviral protease cleavage sequence Ser/Thr-X-Y-Tyr/Phe-Pro are substrates for purified recombinant HIV-1 protease with Kms in the millimolar range. The minimum sequence containing the consensus pentapeptide which serves as a good substrate is a heptapeptide spanning the P4-P3 residues. Substitution of reduced Phe-Pro or Tyr-Pro dipeptide isosteres or the statine analog 3-hydroxy-4-amino-5-phenylpentanoic acid for the scissile dipeptide afforded inhibitors of HIV-1 protease with Ki values in the micromolar range, three orders of magnitude better in affinity than the corresponding substrates. Inhibitors of HIV-1 protease may provide a novel and potentially useful therapeutic approach to the treatment of acquired immune deficiency syndrome (AIDS).

Inhibition of HSV-1 protease by benzoxazinones

Abstract Benzoxazinones have been discovered which are mechanism based inhibitors of HSV-1 protease with micromolar IC 50 values. Formation of a monoadduct consistent with the acyl-enzyme complex was detected by mass spectroscopy. A parallel array synthesis was developed to explore 2-heteroatom substituted SAR.