Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
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Abstract
Here we present the crystal structure of SARS-CoV-2 main protease (M pro ) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of M pro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of M pro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by M pro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by M pro , followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.
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SciScore for 10.1101/2020.05.02.043554: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data analysis was carried out using XDS (20), COOT (21), PHENIX (22), and PanDDA (23), in addition to some bespoke software tools. COOTsuggested: (Coot, RRID:SCR_014222)PHENIXsuggested: (Phenix, RRID:SCR_014224)Data were analysed using MassLynx ( MassLynxsuggested: (MassLynx , RRID:SCR_014271)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We …SciScore for 10.1101/2020.05.02.043554: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Data analysis was carried out using XDS (20), COOT (21), PHENIX (22), and PanDDA (23), in addition to some bespoke software tools. COOTsuggested: (Coot, RRID:SCR_014222)PHENIXsuggested: (Phenix, RRID:SCR_014224)Data were analysed using MassLynx ( MassLynxsuggested: (MassLynx , RRID:SCR_014271)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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