Otto MJ, Reid CD, Garber S, Winslow D, Scarnati H, Lam P; International Conference on AIDS.
Int Conf AIDS.
1993 Jun 6-11; 9: 34 (abstract no. WS-A18-3).
Du Pont Merck Pharmaceutical Company, Glenolden, PA.
OBJECTIVE: Currently the most potent inhibitors of HIV protease are peptidyl in nature. Our objective was to use the crystallographic structural information of HIV-1 protease to design and synthesize novel non-peptidyl inhibitors of the enzyme and to determine their antiviral activity in vitro. METHOD: The antiviral activity of test compounds was determined by yield reduction assays in MT-2, H9 and peripheral blood mononuclear cells. The yield of virus was measured by p24 and by plaque assays and the 90% inhibitory concentrations, IC90s, were calculated from dose response curves. RESULTS: XM323, a representative of a new class of non-peptidyl inhibitors, was identified as a potent inhibitor of HIV-1 and HIV-2 replication in vitro. The compound was equally effective against laboratory strains of HIV-1 and HIV-2 and against AZT sensitive and resistant clinical isolates of HIV-1 with a mean IC90 against all viruses tested of 0.14 +/- 0.06 microM. XM323 was well tolerated by MT-2 and PBM cells in culture with an in vitro therapeutic index of > or = 760. CONCLUSION: XM323 is a potent inhibitor of HIV replication in vitro and represents a new class of de novo designed non-peptidyl inhibitors of HIV-1 protease.
- Acquired Immunodeficiency Syndrome
- Antiviral Agents
- HIV Core Protein p24
- HIV Protease
- In Vitro
- reverse transcriptase, Human immunodeficiency virus 1
From Meeting Abstracts