Specific features of HIV-1 integrase inhibition by bisphosphonate derivatives

• 17 bisphosphonates of 5 different groups were synthesized including 3 earlier unknown.
• 6 compounds inhibited both strand transfer and 3′-processing catalyzed by integrase.
• SAR study has been reported and explained using liquid NMR experiments.
• OH/NH2 in the chelating group switches competitive inhibitor into noncompetitive.

The integration of viral DNA into the cell genome is one of the key steps in the replication cycle of human immunodeficiency virus type 1 (HIV-1). Therefore, the viral enzyme integrase (IN) catalyzing this process is of great interest as a target for new antiviral agents. We performed a structural–functional analysis of five different series of methylenebisphosphonates (BPs), PO3H2–C(R)(X)–PO3H2, as IN inhibitors with the goal of assessing structural elements required for the inhibitory activity. We found that IN is inhibited only by BP bearing a chlorobenzyl substituent R at the bridging carbon of the P–C–P backbone. These BP inhibited both IN-catalyzed reactions with similar efficacies. They were also active toward some INs with mutations characteristic for HIV-1 strains resistant to strand transfer inhibitors. The study of the mechanism of the IN inhibition by various BP showed that it is effected by the nature of the second substituent (X) at the bridging carbon. Among the tested compounds, only the BP with the amino group bound directly to the BP bridging carbon was found to be a noncompetitive inhibitor and, hence, it can be promising for further studies as potential inhibitor of the IN activity within the preintegration complex.

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