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

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 chlorid...

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Bibliographic Details
Published in:MedChemComm 2023-07, Vol.14 (7), p.126-1271
Main Authors: Gil-Moles, Maria, O'Beirne, Cillian, Esarev, Igor V, Lippmann, Petra, Tacke, Matthias, Cinatl, Jindrich, Bojkova, Denisa, Ott, Ingo
Format: Article
Language:English
Subjects:
Antiviral activity
Antiviral agents
Chemistry
Coordination compounds
Drug development
Enzyme kinetics
Inhibitors
Iodides
Ligands
Metal complexes
Papain
Protease
Protease inhibitors
Proteinase
Proteinase inhibitors
Severe acute respiratory syndrome coronavirus 2
Silver
Toxicity
Viral diseases
Zinc
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Summary: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. Silver NHC complexes are potent uncompetitive inhibitors of SARS-CoV-2 PL pro with distinct antiviral efficacy.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d3md00067b