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bioRxiv · 10.1101/2021.03.04.433966

Structural insights into plasticity and discovery of remdesivir metabolite GS-441524 binding in SARS-CoV-2 macrodomain

Ni, X.·Schroeder, M.·Olieric, V.·Sharpe, M. E.·Olmos, V.·Proschak, E.·Merk, D.·Knapp, S.·Chaikuad, A.
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Abstract

The nsP3 macrodomain is a conserved protein interaction module that plays essential regulatory roles in 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 the 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 as well as 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 it provides chemical starting points for future inhibitor development.

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Ni, X., Schroeder, M., Olieric, V., Sharpe, M. E., Olmos, V., Proschak, E., Merk, D., Knapp, S., Chaikuad, A.. 2021-03-04. Structural insights into plasticity and discovery of remdesivir metabolite GS-441524 binding in SARS-CoV-2 macrodomain. https://doi.org/10.1101/2021.03.04.433966

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