Carvalho LAR

References (2)

Title : Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 - Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
Author(s) : Carvalho LAR , Ross B , Fehr L , Bolgi O , Wohrle S , Lum KM , Podlesainski D , Vieira AC , Kiefersauer R , Felix R , Rodrigues T , Lucas SD , Gross O , Geiss-Friedlander R , Cravatt BF , Huber R , Kaiser M , Moreira R
Ref : Angew Chem Int Ed Engl , : , 2022
Abstract : Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.
ESTHER : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedSearch : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedID: 36089535
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : 3-Oxo-beta-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling - Carvalho_2020_ACS.Chem.Biol_15_878
Author(s) : Carvalho LAR , Almeida VT , Brito JA , Lum KM , Oliveira TF , Guedes RC , Goncalves LM , Lucas SD , Cravatt BF , Archer M , Moreira R
Ref : ACS Chemical Biology , 15 :878 , 2020
Abstract : 3-Oxo-beta-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-beta-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-beta-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-beta-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.
ESTHER : Carvalho_2020_ACS.Chem.Biol_15_878
PubMedSearch : Carvalho_2020_ACS.Chem.Biol_15_878
PubMedID: 32176480