Title : A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells - Moore_2022_ACS.Chem.Biol_17_2595 |
Author(s) : Moore KP , Schwaid AG , Tudor M , Park S , Beshore DC , Converso A , Shipe WD , Anand R , Lan P , Moningka R , Rothman DM , Sun W , Chi A , Cornella-Taracido I , Adam GC , Bahnck-Teets C , Carroll SS , Fay JF , Goh SL , Lusen J , Quan S , Rodriguez S , Xu M , Andrews CL , Song C , Filzen T , Li J , Hollenstein K , Klein DJ , Lammens A , Lim UM , Fang Z , McHale C , Li Y , Lu M , Diamond TL , Howell BJ , Zuck P , Balibar CJ |
Ref : ACS Chemical Biology , 17 :2595 , 2022 |
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. |
PubMedSearch : Moore_2022_ACS.Chem.Biol_17_2595 |
PubMedID: 36044633 |
Gene_locus related to this paper: human-DPP8 , human-DPP9 |
Inhibitor | ICeD-1 ICeD-2 |
Gene_locus | ICeD-1 ICeD-2 human-DPP8 human-DPP9 |
Structure | ICeD-1 ICeD-2 human-DPP8 human-DPP9 7SVO 7SVM 7SVN 7SVL |
Moore KP, Schwaid AG, Tudor M, Park S, Beshore DC, Converso A, Shipe WD, Anand R, Lan P, Moningka R, Rothman DM, Sun W, Chi A, Cornella-Taracido I, Adam GC, Bahnck-Teets C, Carroll SS, Fay JF, Goh SL, Lusen J, Quan S, Rodriguez S, Xu M, Andrews CL, Song C, Filzen T, Li J, Hollenstein K, Klein DJ, Lammens A, Lim UM, Fang Z, McHale C, Li Y, Lu M, Diamond TL, Howell BJ, Zuck P, Balibar CJ (2022)
A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells
ACS Chemical Biology
17 :2595
Moore KP, Schwaid AG, Tudor M, Park S, Beshore DC, Converso A, Shipe WD, Anand R, Lan P, Moningka R, Rothman DM, Sun W, Chi A, Cornella-Taracido I, Adam GC, Bahnck-Teets C, Carroll SS, Fay JF, Goh SL, Lusen J, Quan S, Rodriguez S, Xu M, Andrews CL, Song C, Filzen T, Li J, Hollenstein K, Klein DJ, Lammens A, Lim UM, Fang Z, McHale C, Li Y, Lu M, Diamond TL, Howell BJ, Zuck P, Balibar CJ (2022)
ACS Chemical Biology
17 :2595