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Retroviral DNA integration
Our studies focus on the mechanism of human immunodeficiency virus type 1 (HIV-1) integration, an essential step in the viral lifecycle. Retroviruses encode their own integrase protein, and our research borrows from numerous disciplines, including molecular virology and structural biology, to understand mechanistic details of integrase function. Integrase active site inhibitors have been in the clinic since 2007, but until recently their mode of action was largely speculative. Novel X-ray crystal structures of the related spumavirus integrase with its DNA substrate yielded unprecedented details of the structural basis of retroviral DNA integration and, moreover, established how the inhibitors work. Lentiviruses like HIV-1 preferentially target active genes during integration. We established that an interaction between integrase and the cellular chromatin binding protein lens epithelium-derived growth factor (LEDGF) plays a significant role in HIV integration targeting.
We have recently solved the 3-dimensional structure of the LEDGF/p75 integrase-binding domain (IBD) by NMR spectroscopy, as well as the x-ray structure of the IBD bound to the integrase catalytic core domain, the first structure of a host protein bound to a retroviral enzyme. Other studies have elucidated the LEDGF/p75 binding pocket on integrase as a sensitive binding site for allosteric inhibitors, unveiling a new location for targeting of second-generation integrase inhibitors. Current approaches include screening chemical libraries to identify small molecule inhibitors of the protein-protein interaction to evaluate their potential to block HIV-1 replication in cell culture.
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