A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells
Keith P. Moore, Adam G. Schwaid, Matthew Tudor, Sang‐Ho Park, Douglas C. Beshore, Antonella Converso, William D. Shipe, Rajan Anand, Ping Lan, Remond Moningka, Deborah Rothman, Wanying Sun, An Chi, Iván Cornella‐Taracido, Gregory C. Adam, Carolyn Bahnck-Teets, Steven S. Carroll, John F. Fay, Shih Lin Goh, Jeffrey Lusen, Shuo Quan, Silveria Rodriguez, Min Xu, Christine L. Andrews, Cheng Song, Tracey Filzen, Jing Li, Kaspar Hollenstein, Daniel J. Klein, Alfred Lammens, U-Ming Lim, Zhiyu Fang, Carolyn McHale, Yuan Li, Meiqing Lu, Tracy L. Diamond, Bonnie J. Howell, Paul Zuck, Carl J. Balibar
Abstract
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.