For RNA viruses, RNA helicases have long been recognized to play critical roles during virus replication cycles, facilitating proper folding and replication of viral RNAs, therefore representing an ideal target for drug discovery. SARS-CoV-2 helicase, the non-structural protein 13 (nsp13) is a highly conserved protein among all known coronaviruses, and, at the moment, is one of the most explored viral targets to identify new possible antiviral agents. In the present study, we present six diketo acids (DKAs) as nsp13 inhibitors able to block both SARS-CoV-2 nsp13 enzymatic functions. Among them four compounds were able to inhibit viral replication in the low micromolar range, being active also on other human coronaviruses such as HCoV229E and MERS CoV. The experimental investigation of the binding mode revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding mode that was further supported by molecular modelling calculations predicting the binding into an allosteric conserved site located in the RecA2 domain.

Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication / Corona, Angela; Madia, Valentina Noemi; De Santis, Riccardo; Manelfi, Candida; Emmolo, Roberta; Ialongo, Davide; Patacchini, Elisa; Messore, Antonella; Amatore, Donatella; Faggioni, Giovanni; Artico, Marco; Iaconis, Daniela; Talarico, Carmine; Di Santo, Roberto; Lista, Florigio; Costi, Roberta; Tramontano, Enzo. - In: ANTIVIRAL RESEARCH. - ISSN 1872-9096. - 217:(2023). [10.1016/j.antiviral.2023.105697]

Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication

Madia, Valentina Noemi
Co-primo
;
Manelfi, Candida;Ialongo, Davide;Patacchini, Elisa;Messore, Antonella;Amatore, Donatella;Artico, Marco;Di Santo, Roberto;Costi, Roberta
Penultimo
;
2023

Abstract

For RNA viruses, RNA helicases have long been recognized to play critical roles during virus replication cycles, facilitating proper folding and replication of viral RNAs, therefore representing an ideal target for drug discovery. SARS-CoV-2 helicase, the non-structural protein 13 (nsp13) is a highly conserved protein among all known coronaviruses, and, at the moment, is one of the most explored viral targets to identify new possible antiviral agents. In the present study, we present six diketo acids (DKAs) as nsp13 inhibitors able to block both SARS-CoV-2 nsp13 enzymatic functions. Among them four compounds were able to inhibit viral replication in the low micromolar range, being active also on other human coronaviruses such as HCoV229E and MERS CoV. The experimental investigation of the binding mode revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding mode that was further supported by molecular modelling calculations predicting the binding into an allosteric conserved site located in the RecA2 domain.
2023
drug development; helicase; SARS-CoV-2 inhibition; unwinding inhibition; nsp13
01 Pubblicazione su rivista::01a Articolo in rivista
Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication / Corona, Angela; Madia, Valentina Noemi; De Santis, Riccardo; Manelfi, Candida; Emmolo, Roberta; Ialongo, Davide; Patacchini, Elisa; Messore, Antonella; Amatore, Donatella; Faggioni, Giovanni; Artico, Marco; Iaconis, Daniela; Talarico, Carmine; Di Santo, Roberto; Lista, Florigio; Costi, Roberta; Tramontano, Enzo. - In: ANTIVIRAL RESEARCH. - ISSN 1872-9096. - 217:(2023). [10.1016/j.antiviral.2023.105697]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1686714
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