Adam GC

References (3)

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.
ESTHER : Moore_2022_ACS.Chem.Biol_17_2595
PubMedSearch : Moore_2022_ACS.Chem.Biol_17_2595
PubMedID: 36044633
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Profiling Active Enzymes for Polysorbate Degradation in Biotherapeutics by Activity-Based Protein Profiling - Li_2021_Anal.Chem_93_8161
Author(s) : Li X , Chandra D , Letarte S , Adam GC , Welch J , Yang RS , Rivera S , Bodea S , Dow A , Chi A , Strulson CA , Richardson DD
Ref : Analytical Chemistry , 93 :8161 , 2021
Abstract : Polysorbate is widely used to maintain stability of biotherapeutic proteins in pharmaceutical formulation development. Degradation of polysorbate can lead to particle formation in drug products, which is a major quality concern and potential patient risk factor. Enzymatic activity from residual host cell enzymes such as lipases and esterases plays a major role for polysorbate degradation. Their high activity, often at very low concentration, constitutes a major analytical challenge in the biopharmaceutical industry. In this study, we evaluated and optimized the activity-based protein profiling (ABPP) approach to identify active enzymes responsible for polysorbate degradation. Using an optimized chemical probe, we established the first global profile of active serine hydrolases in harvested cell culture fluid (HCCF) for monoclonal antibodies (mAbs) production from two Chinese hamster ovary (CHO) cell lines. A total of eight known lipases were identified by ABPP with enzyme activity information, while only five lipases were identified by a traditional abundance-based proteomics (TABP) approach. Interestingly, phospholipase B-like 2 (PLBL2), a well-known problematic HCP was not found to be active in process-intermediates from two different mAbs. In a proof-of-concept study with downstream samples, phospholipase A2 group VII (PLA2G7) was only identified by ABPP and confirmed to contribute to polysorbate-80 degradation for the first time. The established ABBP approach is approved to be able to identify low-abundance host cell enzymes and fills the gap between lipase abundance and activity, which enables more meaningful polysorbate degradation investigations for biotherapeutic development.
ESTHER : Li_2021_Anal.Chem_93_8161
PubMedSearch : Li_2021_Anal.Chem_93_8161
PubMedID: 34032423
Gene_locus related to this paper: human-PLA2G7

Title : Affinity-based ranking of ligands for DPP-4 from mixtures - Adam_2007_Bioorg.Med.Chem.Lett_17_2404
Author(s) : Adam GC , Meng J , Athanasopoulos J , Zhang X , Chapman KT
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2404 , 2007
Abstract : Affinity-based selection strategies have recently emerged as a complement to traditional high throughput screening for the rapid discovery of lead compounds for the large number of protein targets emerging from--omics technologies. Herein, we describe a method for the ranking of mixtures of ligands by affinity selection and apply it to rank order a set of inhibitors for the enzyme dipeptidyl peptidase IV.
ESTHER : Adam_2007_Bioorg.Med.Chem.Lett_17_2404
PubMedSearch : Adam_2007_Bioorg.Med.Chem.Lett_17_2404
PubMedID: 17337342