The Stalk and 1B Domains Are Required for Porcine Deltacoronavirus Helicase NSP13 to Separate the Double-Stranded Nucleic Acids, and the Deletion of the ZBD Impairs This Activity

Animals, Journal Year: 2025, Volume and Issue: 15(6), P. 865 - 865

Published: March 18, 2025

The nonstructural protein 13 (NSP13) of PDCoV is a highly conservative helicase and plays key roles in viral replication. NSP13 contains zinc-binding domain (ZBD), helical Stalk domain, beta-barrel 1B core domain. However, the specific functions these domains remain largely unknown. Here, we expressed purified wild-type NSP13WT various mutants with deletions, activities proteins were analyzed using multiple methods. We found that NSP13ΔZBD possessed abilities to hydrolyze ATP unwind double-stranded nucleic acids, but unwinding efficiency was lower than NSP13WT. In contrast, NSP13ΔZBD-Stalk, NSP13Δ1B, NSP13ΔZBD-Stalk-1B all lost their activity, not ATPase activity. These results revealed deletion ZBD impaired activity NSP13, critical for separate duplexes. identification each this study helpful gain an in-depth understanding overall providing theoretical basis development antiviral drugs targeting helicase.

Language: Английский

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Repurposing Vancomycin as a Potential Antiviral Agent Against PEDV via nsp13 Helicase Inhibition

Animals, Journal Year: 2025, Volume and Issue: 15(7), P. 923 - 923

Published: March 23, 2025

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious intestinal disease with severe economic impacts on the global swine industry. The non-structural protein 13 (nsp13), viral helicase, is essential for replication, making it promising target antiviral drug development. In this study, through virtual screening and molecular dynamics simulations, Vancomycin, small-molecule also clinically used as an antibacterial agent, was identified to exhibit stable binding affinity PEDV nsp13. NTPase ATP-dependent RNA helicase activities of nsp13 were confirmed in vitro, optimal biochemical reaction conditions its dsRNA unwinding activity established. Further experiments demonstrated that Vancomycin effectively inhibited dual enzymatic reduced infections vitro. This research highlights novel inhibitor nsp13, providing valuable mechanistic insights serving model discovery. While study suggests potential repurposing therapeutic agent against PEDV, further investigations are required evaluate feasibility vivo, particularly terms safety, efficacy, practical applicability.

Language: Английский

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Discovery of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as a new class of SARS-CoV-2 nsp13 inhibitors

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130207 - 130207

Published: March 1, 2025

Language: Английский

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Can Deep Learning Blind Docking Methods be Used to Predict Allosteric Compounds?

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Allosteric compounds offer an alternative mode of inhibition to orthosteric with opportunities for selectivity and noncompetition. Structure-based drug design (SBDD) allosteric introduces complications compared their counterparts; multiple binding sites interest are considered, often is only observed in particular protein conformations. Blind docking methods show potential virtual screening ligands, deep learning methods, such as DiffDock, achieve state-of-the-art performance on protein-ligand complex prediction benchmarks traditional Vina Lin_F9. To this aim, we explore the utility a data-driven platform called minimum distance matrix representation (MDMR) retrospectively predict recently discovered inhibitors complexed Cyclin-Dependent Kinase (CDK) 2. In contrast other representations, it uses residue-residue (or residue-ligand) feature that prioritizes formation interactions. Analysis highlights variety conformations ligand modes, identify intermediate conformation heuristic-based kinase classification do not distinguish. Next, self- cross-docking assess whether can both modes if prospective success conditional selection receptor conformation, respectively. We find combined method, DiffDock followed by Lin_F9 Local Re-Docking (DiffDock + LRD), must be selected pose. summary, work value method outlines challenges SBDD compounds.

Language: Английский

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Variable Inhibition of DNA Unwinding Rates Catalyzed by the SARS-CoV-2 Helicase Nsp13 by Structurally Distinct Single DNA Lesions

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7930 - 7930

Published: July 19, 2024

The SARS-CoV-2 helicase, non-structural protein 13 (Nsp13), plays an essential role in viral replication, translocating the 5' → 3' direction as it unwinds double-stranded RNA/DNA. We investigated impact of structurally distinct DNA lesions on unwinding catalyzed by Nsp13. selected include two benzo[

Language: Английский

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