Structural Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524 Binding in SARS-CoV-2 Macrodomain

Xiaomin Ni; Martin Schröder; Vincent Olieric; May E Sharpe; Victor Hernandez-Olmos; Ewgenij Proschak; Daniel Merk; Stefan Knapp; Apirat Chaikuad

doi:10.1021/acsmedchemlett.0c00684

Structural Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524 Binding in SARS-CoV-2 Macrodomain

ACS Med Chem Lett. 2021 Mar 16;12(4):603-609. doi: 10.1021/acsmedchemlett.0c00684. eCollection 2021 Apr 8.

Authors

Xiaomin Ni^{1

2}, Martin Schröder^{1

2}, Vincent Olieric³, May E Sharpe³, Victor Hernandez-Olmos⁴, Ewgenij Proschak^{2

4}, Daniel Merk², Stefan Knapp^{1

2}, Apirat Chaikuad^{1

2}

Affiliations

¹ Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, 60438 Frankfurt am Main, Germany.
² Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
³ Swiss Light Source, Paul Scherrer Institute, 5232 Villigen, Switzerland.
⁴ Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany.

Abstract

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in the host immune response by recognizing and removing posttranslational ADP-ribosylation sites during SARS-CoV-2 infection. Thus targeting this protein domain may offer a therapeutic strategy to combat current and future virus pandemics. To assist inhibitor development efforts, we report here a comprehensive set of macrodomain crystal structures complexed with diverse naturally occurring nucleotides, small molecules, and nucleotide analogues including GS-441524 and its phosphorylated analogue, active metabolites of remdesivir. The presented data strengthen our understanding of the SARS-CoV-2 macrodomain structural plasticity and provide chemical starting points for future inhibitor development.