New Inhibitors Targeting HIV-1 Integrase During Viral Maturation

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Abstract HIV-1 integrase (IN) is validated clinical target and is essential for viral replication. During the early steps of infection, tetrameric IN associates with two viral DNA ends and catalyzes their integration into the host chromosome. A new class of allosteric IN inhibitors (ALLINIs) has been reported to inhibit enzyme function by promoting aberrant IN multimerization. Interestingly, in infected cells these compounds impaired both early and late stages of HIV-1 replication. In particular, the ALLINI-treated virions were found to display profound viral core morphologies defects similar to those observed with several replication-defective class II IN mutants. Collectively, these studies have suggested that in addition to its known catalytic function in early stage, IN also plays an essential and non-catalytic role during the late stage of HIV-1 replication. We were recently able to discover that IN binds to several viral RNA (vRNA) elements and that ALLINIs strongly modulate these interactions in the virion. In addition, we observed that IN can bring these bound vRNA elements together suggesting a possible role in vRNA condensation. The present application will test the following hypothesis: IN-vRNA interactions and IN oligomerization which are both critical for the correct formation of infectious virions can be targeted by small molecule inhibitors. In aims 1, we will fully characterize the IN-vRNA complex and elucidate the significance of the proper IN multimerization for vRNA binding and particle maturation. In aims 2, we will design new IN inhibitors capable of modulating IN-vRNA binding and particle maturation. Mechanistic and molecular details that will emerge from these studies will guide future drug targeting initiatives of these critical non-catalytic IN functions in late stage of the viral replication.