tetano
Editor, Senior Moderator
J Med Chem
. 2021 Aug 4.
doi: 10.1021/acs.jmedchem.1c00598. Online ahead of print.
Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL [SUP]pro[/SUP])
Sang Hoon Han[SUP] 1 [/SUP], Christopher M Goins[SUP] 1 [/SUP], Tarun Arya[SUP] 1 [/SUP], Woo-Jin Shin[SUP] 2 [/SUP], Joshua Maw[SUP] 1 [/SUP], Alice Hooper[SUP] 1 [/SUP], Dhiraj P Sonawane[SUP] 1 [/SUP], Matthew R Porter[SUP] 1 [/SUP], Breyanne E Bannister[SUP] 3 [/SUP], Rachel D Crouch[SUP] 3 [/SUP], A Abigail Lindsey[SUP] 1 [/SUP], Gabriella Lakatos[SUP] 1 [/SUP], Steven R Martinez[SUP] 1 [/SUP], Joseph Alvarado[SUP] 1 [/SUP], Wendell S Akers[SUP] 3 [/SUP], Nancy S Wang[SUP] 1 [/SUP], Jae U Jung[SUP] 4 5 [/SUP], Jonathan D Macdonald[SUP] 1 [/SUP], Shaun R Stauffer[SUP] 1 [/SUP]
Affiliations
Abstract
Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL[SUP]pro[/SUP]). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL[SUP]pro[/SUP] enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL[SUP]pro[/SUP] inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.
. 2021 Aug 4.
doi: 10.1021/acs.jmedchem.1c00598. Online ahead of print.
Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL [SUP]pro[/SUP])
Sang Hoon Han[SUP] 1 [/SUP], Christopher M Goins[SUP] 1 [/SUP], Tarun Arya[SUP] 1 [/SUP], Woo-Jin Shin[SUP] 2 [/SUP], Joshua Maw[SUP] 1 [/SUP], Alice Hooper[SUP] 1 [/SUP], Dhiraj P Sonawane[SUP] 1 [/SUP], Matthew R Porter[SUP] 1 [/SUP], Breyanne E Bannister[SUP] 3 [/SUP], Rachel D Crouch[SUP] 3 [/SUP], A Abigail Lindsey[SUP] 1 [/SUP], Gabriella Lakatos[SUP] 1 [/SUP], Steven R Martinez[SUP] 1 [/SUP], Joseph Alvarado[SUP] 1 [/SUP], Wendell S Akers[SUP] 3 [/SUP], Nancy S Wang[SUP] 1 [/SUP], Jae U Jung[SUP] 4 5 [/SUP], Jonathan D Macdonald[SUP] 1 [/SUP], Shaun R Stauffer[SUP] 1 [/SUP]
Affiliations
- PMID: 34347470
- DOI: 10.1021/acs.jmedchem.1c00598
Abstract
Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL[SUP]pro[/SUP]). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CL[SUP]pro[/SUP] enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CL[SUP]pro[/SUP] inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.