A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells

  • ACS Chem Biol. 2022 Sep 16;17(9):2595-2604. doi: 10.1021/acschembio.2c00515.
Keith P Moore  1 ,  Adam G Schwaid  1 ,  Matthew Tudor  2 ,  Sangho Park  3 ,  Douglas C Beshore  4 ,  Antonella Converso  4 ,  William D Shipe  4 ,  Rajan Anand  1 ,  Ping Lan  1 ,  Remond Moningka  1 ,  Deborah M Rothman  1 ,  Wanying Sun  1 ,  An Chi  1 ,  Ivan Cornella-Taracido  1 ,  Gregory C Adam  3 ,  Carolyn Bahnck-Teets  3 ,  Steven S Carroll  3 ,  John F Fay  3 ,  Shih Lin Goh  3 ,  Jeffrey Lusen  3 ,  Shuo Quan  3 ,  Silveria Rodriguez  3 ,  Min Xu  3 ,  Christine L Andrews  3 ,  Cheng Song  3 ,  Tracey Filzen  5 ,  Jing Li  5 ,  Kaspar Hollenstein  2 ,  Daniel J Klein  2 ,  Alfred Lammens  6 ,  U-Ming Lim  7 ,  Zhiyu Fang  8 ,  Carolyn McHale  8 ,  Yuan Li  8 ,  Meiqing Lu  8 ,  Tracy L Diamond  8 ,  Bonnie J Howell  8 ,  Paul Zuck  8 ,  Carl J Balibar  8
Affiliations
  • 1. Chemical Biology, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 2. Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 3. Quantitative Biosciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 4. Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 5. Screening and Protein Sciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 6. Proteros Biostructures GmbH, Bunsenstr, Martinsried 82152, Germany.
  • 7. Genome and Biomarker Sciences, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 8. Infectious Disease and Vaccines, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
PMID: 36044633 DOI: 10.1021/acschembio.2c00515
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 (" i nducer of ce ll d eath-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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