Dynamic Combinatorial Chemistry Unveils Nsp10 Inhibitors with Antiviral Potential Against SARS-CoV-2.

Autor: Jumde RP; Global Antibiotic Research and Development Partnership, Discovery and Exploratory Research, SWITZERLAND., Jézéquel G; Helmholtz Institute for Pharmaceutical Research Saarland, Drug Design and Optimisation, GERMANY., Saramago M; Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, PORTUGAL., Frank NA; Helmholtz Institute for Pharmaceutical Research Saarland, Microbial Natural Products, GERMANY., Adam S; Helmholtz Institute for Pharmaceutical Research Saarland, Microbial Natural Products, GERMANY., Cunha MV; Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, PORTUGAL., Bader CD; Helmholtz Institute for Pharmaceutical Research Saarland, Microbial Natural Products, GERMANY., Gunesch AP; TWINCORE Center of Experimental and Clinical Infection Research, Institute for Experimental Virology, GERMANY., Köhler NM; TWINCORE Center of Experimental and Clinical Infection Research, Institute for Experimental Virology, GERMANY., Johannsen S; Helmholtz Institute for Pharmaceutical Research Saarland, Drug Design and Optimisation, GERMANY., Bousis S; Helmholtz Institute for Pharmaceutical Research Saarland, Drug Design and Optimisation, GERMANY., Pietschmann T; TWINCORE Center of Experimental and Clinical Infection Research, Institute for Experimental Virology, GERMANY., Matos RG; Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, PORTUGAL., Müller R; Helmholtz Institute for Pharmaceutical Research Saarland, Microbial Natural Products, GERMANY., Arraiano CM; Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, PORTUGAL., Hirsch AKH; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, GERMANY.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Dec 15, pp. e202403390. Date of Electronic Publication: 2024 Dec 15.
DOI: 10.1002/chem.202403390
Abstrakt: The development of antiviral drugs against the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) responsible for the recent Covid-19 pandemic is crucial, as treatment options remain limited and vaccination does not prevent (re)infection. Two relatively underexplored targets of this virus are the 3'-5' exoribonuclease (ExoN) and the 2'-O-methyltransferase (2'-O-Mtase), both essential for the viral viability. The non-structural protein Nsp14 and Nsp16 exhibit enzymatic activities for ExoN and 2'-O-Mtase, respectively, especially when in complex with their co-factor protein Nsp10. The study focuses on the use of target-directed dynamic combinatorial chemistry (tdDCC) to identify binders of Nsp10, aiming to disturb the protein-protein interactions (PPI) involving Nsp10-Nsp14, as well as Nsp10-Nsp16. We synthesised the hits and evaluated them to assess Nsp10 affinity, ExoN and 2'-O-Mtase activities inhibition, and anti-viral activity in hCoV-229E and SARS-CoV-2 infected whole-cell setting. This study reports a novel class of ExoN and/or 2'-O-Mtase inhibitors exhibiting anti-viral activity against coronaviruses.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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