HIV/AIDS remains a debilitating disease globally, with infections among young adults in the US in recent years increasing. Although extensive efforts are dedicated to HIV vaccine and cure research, these approaches have yet to yield candidates for routine clinical use. By contrast, combination antiretroviral therapy (cART) has been used to reduce disease burden and mortality since its introduction into the clinic in the mid-1990s. Recommended cART formulations contain an integrase inhibitor that inhibits the enzyme active site and its strand transfer activity (integrase strand transfer inhibitor or INSTI). Despite their resounding success, incidence of resistance to second-generation INSTIs is increasing, and will predictably increase further as these drugs are rolled out for global usage. Paralleling the success of active site and allosteric site inhibitors of the reverse transcriptase enzyme, the clinic will benefit greatly from the addition of a second class of integrase inhibitor, such as allosteric integrase inhibitors (ALLINIs). This grant over the current funding cycle made seminal contributions to understanding the mechanism of action of pre-clinical ALLINI compounds, and such compounds are today in development at pharmaceutical companies. In this grant application we will continue to categorize the mechanism of ALLINI action, which is critical basic information required in advance of clinical rollout and clinical drug resistance. This research will in part be focused on the mechanism of action of the integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75, which helps to guide the virus to active genes for integration. In particular, some of the best-studied ALLINI chemotypes are effective inhibitors of the LEDGF/p75-integrase binding interaction. Inspired by the success of LEDGF/75 binding site ALLINI compounds, we will now characterize in detail interactions of additional host factors that are shown to bind integrase. As evidenced by the large variety of mutations that cause pleiotropic replication catastrophe, HIV-1 integrase is extremely sensitive to change. Characterization of novel host factor-integrase complexes will define new targets for future antiretroviral inhibitor development.
Allosteric integrase inhibitors are a promising class of antiretroviral drug compounds. Herein we will elucidate the mechanism of allosteric integrase inhibitor drug action in part focusing on the host cell factor LEDGF, and characterize new complexes between integrase and host factors with the goal to define new targets for future drug development.
|Engelman, Alan N; Singh, Parmit K (2018) Cellular and molecular mechanisms of HIV-1 integration targeting. Cell Mol Life Sci 75:2491-2507|
|El Ashkar, Sara; Schwaller, Juerg; Pieters, Tim et al. (2018) LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. Blood 131:95-107|
|Alvarez, Frances J D; He, Shaoda; Perilla, Juan R et al. (2017) CryoEM structure of MxB reveals a novel oligomerization interface critical for HIV restriction. Sci Adv 3:e1701264|
|Hoyte, Ashley C; Jamin, Augusta V; Koneru, Pratibha C et al. (2017) Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing. J Biol Chem 292:19814-19825|
|Lesbats, Paul; Engelman, Alan N; Cherepanov, Peter (2016) Retroviral DNA Integration. Chem Rev 116:12730-12757|
|Serrao, Erik; Cherepanov, Peter; Engelman, Alan N (2016) Amplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites. J Vis Exp :|
|Serrao, Erik; Engelman, Alan N (2016) Sites of retroviral DNA integration: From basic research to clinical applications. Crit Rev Biochem Mol Biol 51:26-42|
|Engelman, Alan; Cherepanov, Peter (2014) Retroviral Integrase Structure and DNA Recombination Mechanism. Microbiol Spectr 2:|
|Slaughter, Alison; Jurado, Kellie A; Deng, Nanjie et al. (2014) The mechanism of H171T resistance reveals the importance of N?-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase. Retrovirology 11:100|
|Wang, Hao; Shun, Ming-Chieh; Li, Xiang et al. (2014) Efficient Transduction of LEDGF/p75 Mutant Cells by Gain-of-Function HIV-1 Integrase Mutant Viruses. Mol Ther Methods Clin Dev 1:|
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