Inhibition of NF-kappa B-dependent HIV-1 replication by the marine natural product bengamide A

摘要

HIV-1 inhibitors that act by mechanisms distinct from existing antiretrovirals can provide novel insights into viral replication and potentially inform development of new therapeutics. Using a multi-cycle HIV-1 replication assay, we screened 252 pure compounds derived from marine invertebrates and microorganisms and identified 6 (actinomycin Z(2), bastadin 6, bengamide A, haliclonacyclamine A + B, keramamine C, neopetrosiamide B) that inhibited HIV-1 with 50% effective concentrations (EC(50)s) of 3.8 mu M or less. The most potent inhibitor, bengamide A, blocked HIV-1 in a T cell line with an EC50 of 0.015 mu M and in peripheral blood mononuclear cells with an EC50 of 0.032 mu M. Bengamide A was previously described to inhibit NF-kappa B signaling. Consistent with this mechanism, bengamide A suppressed reporter expression from an NF-kappa B-driven minimal promoter and an HIV-1 long terminal repeat (LTR) with conserved NF-kappa B response elements, but lacked activity against an LTR construct with mutation of these elements. In single-cycle HIV-1 infection assays, bengamide A also suppressed viral protein expression when viruses encoded an intact LTR but exhibited minimal activity against those with mutated NF-kappa B elements. Finally, bengamide A did not inhibit viral DNA accumulation, indicating that it likely acts downstream of this step in HIV-1 replication. Our study identifies multiple new antiviral compounds including an unusually potent inhibitor of HIV-1 gene expression.