7SVN

DPP9 IN COMPLEX WITH LIGAND ICeD-1

Summary for 7SVN

• Entry DOI: 10.2210/pdb7svn/pdb
• Descriptor: Dipeptidyl peptidase 9, (2S,4S)-1-[(2S)-2-amino-2-cyclohexylacetyl]-4-fluoropyrrolidine-2-carbonitrile (3 entities in total)
• Functional Keywords: dipeptidyl peptidase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 397866.11

Authors

Lammens, A.,Hollenstein, K.,Klein, D.J. (deposition date: 2021-11-19, release date: 2022-10-05, Last modification date: 2024-10-30)

Primary citation

Moore, K.P.,Schwaid, A.G.,Tudor, M.,Park, S.,Beshore, D.C.,Converso, A.,Shipe, W.D.,Anand, R.,Lan, P.,Moningka, R.,Rothman, D.M.,Sun, W.,Chi, A.,Cornella-Taracido, I.,Adam, G.C.,Bahnck-Teets, C.,Carroll, S.S.,Fay, J.F.,Goh, S.L.,Lusen, J.,Quan, S.,Rodriguez, S.,Xu, M.,Andrews, C.L.,Song, C.,Filzen, T.,Li, J.,Hollenstein, K.,Klein, D.J.,Lammens, A.,Lim, U.M.,Fang, Z.,McHale, C.,Li, Y.,Lu, M.,Diamond, T.L.,Howell, B.J.,Zuck, P.,Balibar, C.J.
A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells.
Acs Chem.Biol., 17:2595-2604, 2022

PubMed 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 ("nducer of ll 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.

PubMed: 36044633
DOI: 10.1021/acschembio.2c00515

Experimental method

X-RAY DIFFRACTION (2.78 Å)