tetano
Editor, Senior Moderator
Bioorg Med Chem
. 2022 May 11;67:116788.
doi: 10.1016/j.bmc.2022.116788. Online ahead of print.
Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain
Lavinia M Sherrill[SUP] 1 [/SUP], Elva E Joya[SUP] 1 [/SUP], AnnMarie Walker[SUP] 1 [/SUP], Anuradha Roy[SUP] 2 [/SUP], Yousef M Alhammad[SUP] 3 [/SUP], Moriama Atobatele[SUP] 2 [/SUP], Sarah Wazir[SUP] 4 [/SUP], George Abbas[SUP] 1 [/SUP], Patrick Keane[SUP] 1 [/SUP], Junlin Zhuo[SUP] 5 [/SUP], Anthony K L Leung[SUP] 6 [/SUP], David K Johnson[SUP] 7 [/SUP], Lari Lehtiö[SUP] 4 [/SUP], Anthony R Fehr[SUP] 8 [/SUP], Dana Ferraris[SUP] 9 [/SUP]
Affiliations
Abstract
A series of amino acid based 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to discern the structure activity relationships against the SARS-CoV-2 nsp3 macrodomain (Mac1), an ADP-ribosylhydrolase that is critical for coronavirus replication and pathogenesis. Structure activity studies identified compound 15c as a low-micromolar inhibitor of Mac1 in two ADP-ribose binding assays. This compound also demonstrated inhibition in an enzymatic assay of Mac1 and displayed a thermal shift comparable to ADPr in the melting temperature of Mac1 supporting binding to the target protein. A structural model reproducibly predicted a binding mode where the pyrrolo pyrimidine forms a hydrogen bonding network with Asp[SUP]22[/SUP] and the amide backbone NH of Ile[SUP]23[/SUP] in the adenosine binding pocket and the carboxylate forms hydrogen bonds to the amide backbone of Phe[SUP]157[/SUP] and Asp[SUP]156[/SUP], part of the oxyanion subsite of Mac1. Compound 15c also demonstrated notable selectivity for coronavirus macrodomains when tested against a panel of ADP-ribose binding proteins. Together, this study identified several low MW, low µM Mac1 inhibitors to use as small molecule chemical probes for this potential anti-viral target and offers starting points for further optimization.
Keywords: ADP-ribosylation; COVID-19; Coronavirus; Nsp3 macrodomain inhibitors; SARS-CoV-2
. 2022 May 11;67:116788.
doi: 10.1016/j.bmc.2022.116788. Online ahead of print.
Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain
Lavinia M Sherrill[SUP] 1 [/SUP], Elva E Joya[SUP] 1 [/SUP], AnnMarie Walker[SUP] 1 [/SUP], Anuradha Roy[SUP] 2 [/SUP], Yousef M Alhammad[SUP] 3 [/SUP], Moriama Atobatele[SUP] 2 [/SUP], Sarah Wazir[SUP] 4 [/SUP], George Abbas[SUP] 1 [/SUP], Patrick Keane[SUP] 1 [/SUP], Junlin Zhuo[SUP] 5 [/SUP], Anthony K L Leung[SUP] 6 [/SUP], David K Johnson[SUP] 7 [/SUP], Lari Lehtiö[SUP] 4 [/SUP], Anthony R Fehr[SUP] 8 [/SUP], Dana Ferraris[SUP] 9 [/SUP]
Affiliations
- PMID: 35597097
- PMCID: PMC9093066
- DOI: 10.1016/j.bmc.2022.116788
Abstract
A series of amino acid based 7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to discern the structure activity relationships against the SARS-CoV-2 nsp3 macrodomain (Mac1), an ADP-ribosylhydrolase that is critical for coronavirus replication and pathogenesis. Structure activity studies identified compound 15c as a low-micromolar inhibitor of Mac1 in two ADP-ribose binding assays. This compound also demonstrated inhibition in an enzymatic assay of Mac1 and displayed a thermal shift comparable to ADPr in the melting temperature of Mac1 supporting binding to the target protein. A structural model reproducibly predicted a binding mode where the pyrrolo pyrimidine forms a hydrogen bonding network with Asp[SUP]22[/SUP] and the amide backbone NH of Ile[SUP]23[/SUP] in the adenosine binding pocket and the carboxylate forms hydrogen bonds to the amide backbone of Phe[SUP]157[/SUP] and Asp[SUP]156[/SUP], part of the oxyanion subsite of Mac1. Compound 15c also demonstrated notable selectivity for coronavirus macrodomains when tested against a panel of ADP-ribose binding proteins. Together, this study identified several low MW, low µM Mac1 inhibitors to use as small molecule chemical probes for this potential anti-viral target and offers starting points for further optimization.
Keywords: ADP-ribosylation; COVID-19; Coronavirus; Nsp3 macrodomain inhibitors; SARS-CoV-2