Author: Quan, Shuo ; Adam, Gregory C. ; Schwaid, Adam G. ; Hollenstein, Kaspar ; Diamond, Tracy L. ; Anand, Rajan ; Carroll, Steven S. ; Moningka, Remond ; Beshore, Douglas C. ; Moore, Keith P. ; Goh, Shih Lin ; Shipe, William D. ; Rothman, Deborah M. ; Lim, U-Ming ; Howell, Bonnie J. ; Tudor, Matthew ; Xu, Min ; Klein, Daniel J. ; Fay, John F. ; Rodriguez, Silveria ; Lammens, Alfred ; Li, Jing ; Cornella-Taracido, Ivan ; Lan, Ping ; Park, Sangho ; Lu, Meiqing ; Zuck, Paul ; Converso, Antonella ; Filzen, Tracey ; McHale, Carolyn ; Li, Yuan ; Fang, Zhiyu ; Andrews, Christine L. ; Balibar, Carl J. ; Song, Cheng ; Chi, An ; Lusen, Jeffrey ; Sun, Wanying ; Bahnck-Teets, Carolyn

Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	United States	Merck & Co., Inc.	31 Aug 2022
HIV Infections	Preclinical	Germany	Proteros biostructures GmbH	31 Aug 2022

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