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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the rapidly evolving RNA virus behind the COVID-19 pandemic, has spawned numerous variants since its 2019 emergence. The multifunctional Nonstructural protein 14 (NSP14) enzyme, possessing exonuclease and messenger RNA (mRNA) capping capabilities, serves as a key player. Notably, single and co-occurring mutations within NSP14 significantly influence replication fidelity and drive variant diversification. This study comprehensively examines 120 co-mutations, 68 unique mutations, and 160 conserved residues across NSP14 homologs, shedding light on their implications for phylogenetic patterns, pathogenicity, and residue interactions. Quantitative physicochemical analysis categorizes 3953 NSP14 variants into three clusters, revealing genetic diversity. This research underscoresthe dynamic nature of SARS-CoV-2 evolution, primarily governed by NSP14 mutations. Understanding these genetic dynamics provides valuable insights for therapeutic and vaccine development.
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http://dx.doi.org/10.1016/j.compbiomed.2023.107899 | DOI Listing |
Vet Microbiol
September 2025
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai 200240, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou Unive
Bovine coronavirus (BCoV), a member of the Betacoronavirus genus, causes severe calf gastroenteritis and respiratory disease, resulting in a significant loss of livestock. Coronavirus non-structural protein 14 (nsp14) is involved in viral RNA replication and modification and subverts host immune regulatory pathways to facilitate immune evasion. In this study, we demonstrated that BCoV nsp14 mediates TNF receptor-associated factor 3 (TRAF3) degradation through the coordinated targeting of the ubiquitin-proteasome and autophagy-lysosomal pathways, thereby potentiating viral replication.
View Article and Find Full Text PDFJ Virol
September 2025
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Feline infectious peritonitis virus (FIPV) can cause an immune-mediated disease that is fatal to felines, but there is a lack of clinically effective protection conferred by vaccines. The methyltransferase (MTase) activity of the coronavirus nonstructural proteins nsp14 and nsp16 affects virulence, but there are no studies on the effect of nsp14 and nsp16 mutations affecting enzyme activity on the virulence of FIPV. In this study, we successfully rescued two mutant strains based on the previous infectious clone QS-79, named FIPV QS-79 dnsp14 and dnsp16, by mutating the MTase active sites of nsp14 (N415) and nsp16 (D129).
View Article and Find Full Text PDFRSC Med Chem
August 2025
Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz Staudinger Weg 5 55128 Mainz Germany
Parallel syntheses and their throughput capabilities are powerful tools for the rapid generation of molecule libraries, making them highly beneficial for accelerating hit identification in early-stage drug discovery. Utilizing chemical spaces and virtual libraries enhances time and cost efficiency, enabling the faster exploitation of chemically diverse compounds. In this study, a parallel synthesis method for rapidly generating a 5'-amino-5'-deoxy adenosine-based amide and sulfonamide library of 42 compounds is described with high yields and purity, which is economical and ecological due to the reduced requirements for extensive purification.
View Article and Find Full Text PDFJ Med Chem
September 2025
Sanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity.
View Article and Find Full Text PDFJ Med Virol
September 2025
Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.
RNA viruses have high mutation frequency, quick generation periods and vast population numbers, which promote fast evolution and host environment adaptation. We integrated scRNA-seq and spatial transcriptomics to profile immune cells and viral gene expression in COVID-19. Cell types and interactions were identified using Seurat-based tools.
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