Synthesis of Structural ADP-Ribose Analogues as Inhibitors for SARS-CoV-2 Macrodomain 1

  • Org Lett. 2024 Jul 12;26(27):5700-5704. doi: 10.1021/acs.orglett.4c01792.
Koen J Rijpkema  1 ,  Marion Schuller  2 ,  Miriam S van der Veer  1 ,  Sjoerd Rieken  1 ,  Diego L R Chang  1 ,  Pascal Balić  1 ,  Alex Todorov  1 ,  Hugo Minnee  1 ,  Sven Wijngaarden  1 ,  Isaac A Matos  2  3 ,  Nicolas C Hoch  3 ,  Jeroen D C Codée  1 ,  Ivan Ahel  2 ,  Dmitri V Filippov  1
Affiliations
  • 1. Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
  • 2. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom.
  • 3. Departamento de Bioquímica, Instituto de Química, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, Sao Paulo 055800-000, Brasil.
PMID: 38935522 DOI: 10.1021/acs.orglett.4c01792
Abstract

Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, a prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, a relatively underexplored angle in design pertains to the synthesis of structural substrate mimics. Here, we present the synthesis and biophysical activity of novel adenosine diphosphate ribose (ADPr) analogues as SARS-CoV-2 NSP3 Mac1 inhibitors.

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