Inhibition of the early phase of HIV replication by an isothiazolone, PD 161374

A new class of substituted 2 ' -benzisothiazolone represented by PD 161374 was discovered with antiviral activity against retroviruses similar to previously described nucleocapsid inhibitor PD 159206 (DIBA-4), In T cell culture, the 50% inhibitory concentrations (EC50) of PD 161374 and PD 159206 were on average 2.5 muM (ranges of 1.2-13.5 muM) without any cytotoxic effect up to 100 muM. PD 161374 inhibited acute HIV infection and it was effective when added during the early phase of HIV infection. However, very modest effects were observed in chronically infected H9 cells and the HIV latency model line OM-10.1. Direct PCR analysis of infected cells demonstrated that PD 161374 delayed the appearance of completed HIV-cDNA. products including 2LTR circles. Together all these results suggest that PD 161374 exerts its antiviral effect at pre-integration steps in the early phase of the Virus life cycle. When combined with a protease inhibitor, PD 161374 did not show any antagonism and combination with a reverse transcriptase inhibitor (AZT) resulted in a synergistic effect. (C) 2001 Elsevier Science B.V. All rights reserved.