Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2.

Autor:	Gil-Moles M; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany ingo.ott@tu-bs.de.; Departamento de Química, Universidad de La Rioja, Centro de Investigación de Síntesis Química (CISQ), Complejo Científico Tecnológico 26004 Logroño Spain., O'Beirne C; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany ingo.ott@tu-bs.de., Esarev IV; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany ingo.ott@tu-bs.de., Lippmann P; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany ingo.ott@tu-bs.de., Tacke M; School of Chemistry, University College Dublin Belfield Dublin 4 Ireland., Cinatl J Jr; Institute of Medical Virology, Universitätsklinikum Frankfurt Paul-Ehrlich-Str. 40 60596 Frankfurt Germany., Bojkova D; Institute of Medical Virology, Universitätsklinikum Frankfurt Paul-Ehrlich-Str. 40 60596 Frankfurt Germany., Ott I; Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig Beethovenstr. 55 38106 Braunschweig Germany ingo.ott@tu-bs.de.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2023 May 16; Vol. 14 (7), pp. 1260-1271. Date of Electronic Publication: 2023 May 16 (Print Publication: 2023).
DOI:	10.1039/d3md00067b
Abstrakt:	The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as antiviral agents in general and in particular against SARS-CoV-2. Here we report on silver NHC complexes with chloride or iodide counter ligands that are potent inhibitors of the SARS-CoV-2 papain-like protease (PL pro ) but inactive against 3C-like protease (3CL pro ) as another SARS-CoV-2 protease. Mechanistic studies on a selected complex confirmed zinc removal from a zinc binding domain of PL pro as relevant factor of their activity. In addition, enzyme kinetic experiments revealed that the complex is an uncompetitive inhibitor and with this rare type of inhibition it offers great pharmacological advantages in terms selectivity. The silver NHC complexes with iodide ligands showed very low or absent host cell toxicity and triggered strong effects on viral replication in cells infected with SARS-CoV-2, making them promising future antiviral drug candidates. Competing Interests: There is no conflict of interest to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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