Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 4, Pages 603-609Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00684
Keywords
Macrodomain; SARS-CoV-2; remdesivir; ADP-ribosylation; structure based design
Categories
Funding
- Goethe University Frankfurt under the Goethe-Corona-Fonds program
- SGC
- AbbVie [1097737]
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond
- Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN) [875510]
- Janssen
- Merck KGaA (EMD in Canada)
- Merck KGaA (EMD in U.S.)
- Merck & Co (MSD outside Canada)
- Merck & Co (MSD outside U.S.)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome [106169/ZZ14/Z]
- Fraunhofer Internal Programs [Anti-Corona 164-600014]
- Deutsche Forschungsgemeinschaft (DFG, Heisenberg-Professur) [PR1405/7-1]
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The nsP3 macrodomain is crucial in regulating the host immune response during SARS-CoV-2 infection by recognizing and removing posttranslational ADP-ribosylation sites. Targeting this protein domain could provide a therapeutic strategy for combating virus pandemics. Crystal structures complexed with diverse nucleotides, small molecules, and nucleotide analogues, including active metabolites of remdesivir, provide valuable insights for inhibitor development.
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.
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