The main protease (M, 3CL) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure-activity relationships of novel small-molecule thioesters as SARS-CoV-2 M inhibitors. Compounds and exhibited excellent SARS-CoV-2 M inhibition with / of 58,700 M s ( = 0.0141 μM) and 27,200 M s ( = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds , , , , , and displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of and with SARS-CoV-2 M was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the M of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00636 | DOI Listing |
Emerg Microbes Infect
December 2025
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
The nuclear-cytoplasmic trafficking of matrix proteins (M) is essential for henipavirus budding, with M protein ubiquitination playing a pivotal role in this dynamic process. Despite its importance, the intricacies of the M ubiquitination cascade have remained elusive. In this study, we elucidate a novel mechanism by which Nipah virus (NiV), a highly pathogenic henipavirus, utilizes a ubiquitination complex involving the E2 ubiquitin-conjugating enzyme RAD6A and the E3 ubiquitin ligase RAD18 to ubiquitinate the virus's M protein, thereby facilitating its nuclear-cytoplasmic trafficking.
View Article and Find Full Text PDFTalanta
November 2024
School of Chemistry and Chemical Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, 210094, China. Electronic address:
The widespread adoption of small-molecule fluorescence detection methodologies in scientific research and industrial contexts can be ascribed to their inherent merits, including elevated sensitivity, exceptional selectivity, real-time detection capabilities, and non-destructive characteristics. In recent years, there has been a growing focus on small-molecule fluorescent probes engineered with sulfur elements, aiming to detect a diverse array of biologically active species. This review presents a comprehensive survey of sulfur-based fluorescent probes published from 2017 to 2023.
View Article and Find Full Text PDFBioorg Med Chem Lett
September 2024
Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan. Electronic address:
For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect.
View Article and Find Full Text PDFFront Pharmacol
March 2024
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, United States.
Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based screen using organoids from wildtype and (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis.
View Article and Find Full Text PDFBackground: Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development.
Methods: We developed a novel morphology-based screen using organoids from wildtype and p48 (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA).
Results: Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis.
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