The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5 ' to 3 ' direction and acts in concert with the replication-transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme's binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.

Romeo, I., Ambrosio, F.a., Costa, G., Corona, A., Alkhatib, M., Salpini, R., et al. (2022). Targeting SARS-CoV-2 nsp13 Helicase and Assessment of Druggability Pockets: Identification of Two Potent Inhibitors by a Multi-Site In Silico Drug Repurposing Approach. MOLECULES, 27(21), 7522 [10.3390/molecules27217522].

Targeting SARS-CoV-2 nsp13 Helicase and Assessment of Druggability Pockets: Identification of Two Potent Inhibitors by a Multi-Site In Silico Drug Repurposing Approach

Salpini, Romina;Svicher, Valentina;Santoro, Maria;Ceccherini-Silberstein, Francesca;
2022-11-03

Abstract

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5 ' to 3 ' direction and acts in concert with the replication-transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme's binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.
3-nov-2022
In corso di stampa
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
SARS-CoV-2 (COVID-19)
conservation analysis
drug repurposing
helicase
inhibitory activity
nsp13
Humans
Drug Repositioning
RNA Helicases
Viral Nonstructural Proteins
DNA Helicases
Antiviral Agents
SARS-CoV-2
COVID-19
Romeo, I., Ambrosio, F.a., Costa, G., Corona, A., Alkhatib, M., Salpini, R., et al. (2022). Targeting SARS-CoV-2 nsp13 Helicase and Assessment of Druggability Pockets: Identification of Two Potent Inhibitors by a Multi-Site In Silico Drug Repurposing Approach. MOLECULES, 27(21), 7522 [10.3390/molecules27217522].
Romeo, I; Ambrosio, Fa; Costa, G; Corona, A; Alkhatib, M; Salpini, R; Lemme, S; Vergni, D; Svicher, V; Santoro, M; Tramontano, E; Ceccherini-Silberste...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/308900
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