Three New Potent HIV-1 Inhibitors from Myxobacteria

Abstract

Three novel compounds, namely, phenoxan, phenalamide A1, and thiangazole, were found to suppress HIV-1 replication in cell cultures. The compounds were discovered by screening crude extracts from myxobacteria and were isolated from two strains of Polyangium sp. and a strain of Myxococcus stipitatus. Their structures have been elucidated. The cytotoxic concentrations for MT-4 cells were 6.6 μM for phenoxan, 102 μM for phenalamide A1, and 4.7 μM for thiangazole. Phenoxan inhibited the HIV-1-dependent cell death at concentrations of as low as 6.6 nM. Phenalamide A1 could prevent the HIV-1 infection of MT-4 cells even at concentrations of 1.02nM, and thiangazole at 4.7 pM. In our assay thiangazole is at least 100 times more active than AZT. The compounds could not prevent syncythia formation induced by HIV-1. However, like HEPT (Baba et al., 1989; Miyasaka et al., 1989) and TIBO (Pauwels et al., 1990) derivatives they are highly specific since they could not interfere with HIV-2ben dependent MT-4 cell death. HIV-1 RT activity was inhibited by 50% by 376 μM phenoxan, 386 μM phenalamid A1, or 263 μM thiangazole. Since these concentrations are approximately 50000 times higher than their minimum concentrations active in cell cultures, RT-inhibition does not appear to be the major mechanism of HIV-inhibition of the new agents.