Epoxides are an established class of electrophilic alkylating agents that react with nucleophilic protein residues. We report αβ,α'β'-diepoxyketones (DEKs) as a new type of mechanism-based inhibitors of nucleophilic cysteine enzymes. Studies with the L,D-transpeptidase Ldt from and the main protease from SARS-CoV-2 (M) reveal that following epoxide ring opening by a nucleophilic cysteine, further reactions can occur, leading to irreversible alkylation.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601815 | PMC |
| http://dx.doi.org/10.1039/d3cc02932h | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Cell-Active, Arginine-Targeting Irreversible Covalent Inhibitors for Non-Kinases and Kinases.
Angew Chem Int Ed Engl
January 2025
Sun Yat-sen University - Shenzhen Campus, School of Pharmaceutical Sciences (Shenzhen), CHINA.
Targeted covalent inhibitors (TCIs) play an essential role in the fields of kinase research and drug discovery. Most existing TCIs are however cysteine- or lysine-reactive, thus severely limiting their potential applications. New types of TCIs capable of covalently targeting other nucleophilic amino acids that are readily available in proteins are urgently needed.
View Article and Find Full Text PDFDiscovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor.
J Med Chem
January 2025
Department of Discovery Chemistry, Incyte Research Institute, Incyte Corporation, Wilmington, Delaware 19803 United States.
The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, as evidenced by the clinical success of KRAS G12C inhibitors. KRAS G12D, the most common mutant, promises significant expansion of the addressable patient population; however, the reduced nucleophilicity of aspartate compared to cysteine poses significant challenges in balancing sufficient potency with ADME properties to support oral exposure. Herein, we describe the discovery of KRAS G12D inhibitor (), which achieves oral exposure in nonhuman primate (NHP).
View Article and Find Full Text PDFStructural and kinetic characterization of DUSP5 with a Di-phosphorylated tripeptide substrate from the ERK activation loop.
Front Chem Biol
August 2024
Center for Structure-based Drug Design and Development, Department of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI, United States.
Introduction: Dual specific phosphatases (DUSPs) are mitogen-activated protein kinase (MAPK) regulators, which also serve as drug targets for treating various vascular diseases. Previously, we have presented mechanistic characterizations of DUSP5 and its interaction with pERK, proposing a dual active site.
Methods: Herein, we characterize the interactions between the DUSP5 phosphatase domain and the pT-E-pY activation loop of ERK2, with specific active site assignments.
Column Screening and Development of HILIC and RPLC Methods Coupled to Tandem Mass Spectrometry for the Monitoring of Albumin on Cysteine 34 Exposed to Mustard Agents.
J Sep Sci
January 2025
Department of Analytical, Bioanalytical Sciences and Miniaturization (LSABM) Chemistry, Biology and Innovation (CBI), UMR CNRS-ESPCI Paris 8231, ESPCI Paris, PSL University, CNRS, Paris, France.
Adduction on protein nucleophile sites by mustard agents can be monitored to assess detection of retrospective exposure to these agents. Cysteine 34 (Cys34) on human serum albumin was selected as the target of choice. This work targets di- and tripeptides adducted on Cys34 by sulfur mustard, sesquimustard, and nitrogen mustards separated in hydrophilic liquid chromatography (HILIC) and Reversed-Phase (RP) mode.
View Article and Find Full Text PDFCySP3-96 enables scalable, streamlined, and low-cost sample preparation for cysteine chemoproteomic applications.
Mol Cell Proteomics
December 2024
Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA; Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA; DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, CA, 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA. Electronic address:
Cysteine chemoproteomic screening platforms are widely utilized for chemical probe and drug discovery campaigns. Chemoproteomic compound screens, which use a mass spectrometry-based proteomic readout, can interrogate the structure activity relationship (SAR) for thousands of proteins in parallel across the proteome. The versatility of chemoproteomic screens has been demonstrated across electrophilic, nucleophilic, and reversible classes of molecules.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!