tetano
Editor, Senior Moderator
Antiviral Res
. 2022 Nov 3;105458.
doi: 10.1016/j.antiviral.2022.105458. Online ahead of print.
Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404
Montserrat Fàbrega-Ferrer[SUP] 1 [/SUP], Alejandra Herrera-Morandé[SUP] 1 [/SUP], Sara Muriel-Goñi[SUP] 1 [/SUP], Julia Pérez-Saavedra[SUP] 1 [/SUP], Paula Bueno[SUP] 2 [/SUP], Victoria Castro[SUP] 2 [/SUP], Urtzi Garaigorta[SUP] 2 [/SUP], Pablo Gastaminza[SUP] 2 [/SUP], Miquel Coll[SUP] 3 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M[SUP]pro[/SUP]), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M[SUP]pro[/SUP] and SARS-CoV-2 M[SUP]pro[/SUP] and of rupintrivir in complex with SARS-CoV-2 M[SUP]pro[/SUP] were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC[SUB]50[/SUB] values of 47 μM and 101 μM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M[SUP]pro[/SUP]. Equivalent IC[SUB]50[/SUB] values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 μM vs. 66 μM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.
Keywords: AG7404; Human coronavirus; Main protease M(pro); Rupintrivir; SARS-CoV-1; SARS-CoV-2.
. 2022 Nov 3;105458.
doi: 10.1016/j.antiviral.2022.105458. Online ahead of print.
Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404
Montserrat Fàbrega-Ferrer[SUP] 1 [/SUP], Alejandra Herrera-Morandé[SUP] 1 [/SUP], Sara Muriel-Goñi[SUP] 1 [/SUP], Julia Pérez-Saavedra[SUP] 1 [/SUP], Paula Bueno[SUP] 2 [/SUP], Victoria Castro[SUP] 2 [/SUP], Urtzi Garaigorta[SUP] 2 [/SUP], Pablo Gastaminza[SUP] 2 [/SUP], Miquel Coll[SUP] 3 [/SUP]
Affiliations
- PMID: 36336176
- DOI: 10.1016/j.antiviral.2022.105458
Abstract
Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M[SUP]pro[/SUP]), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M[SUP]pro[/SUP] and SARS-CoV-2 M[SUP]pro[/SUP] and of rupintrivir in complex with SARS-CoV-2 M[SUP]pro[/SUP] were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC[SUB]50[/SUB] values of 47 μM and 101 μM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M[SUP]pro[/SUP]. Equivalent IC[SUB]50[/SUB] values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 μM vs. 66 μM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.
Keywords: AG7404; Human coronavirus; Main protease M(pro); Rupintrivir; SARS-CoV-1; SARS-CoV-2.