INHIBITORS OF THE PROTEASE FROM HUMAN-IMMUNODEFICIENCY-VIRUS - SYNTHESIS, ENZYME-INHIBITION, AND ANTIVIRAL ACTIVITY OF A SERIES OF COMPOUNDS CONTAINING THE DIHYDROXYETHYLENE TRANSITION-STATE ISOSTERE

A number of potential HIV protease inhibitory peptides that contain th e dihydroxyethylene isostere were prepared and evaluated for their enz yme binding affinity and antiviral activity in cell cultures. From the template of a previously reported active peptide A, modifications at the N- and C-terminal groups were assessed for potential maintenance o f good inhibitory activity of the resulting peptides. Among the active peptides found, peptide XVIII exhibited potent enzyme inhibitory acti vity. Interestingly, the previously reported, effective 1(S)-amino-2(R )-hydroxyindan C-terminal group for the preparation of very active HIV protease inhibitory peptides could not be applied to the template of peptide XVIII. Molecular modeling of peptide XVIII was studied using t he X-ray crystal structure of peptide A as a starting point in order t o study the likely conformation of peptide XVIII in the active-site cl eft. Relative binding conformations of peptide A and XVIII were obtain ed, although the reason for poor binding affinity for a number of cong eneric peptides in this report was not straightforwardly apparent. Mor e importantly, however, peptide XVIII was found to exhibit more effect ive antiviral activity in the HIV-1/PBMC assay than the reference pept ide A which was previously reported to be approximately equal in effic acy to the reverse transcriptase inhibitor AZT in this assay.