2. Academic Validation
  3. Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design

Pyrimidone inhibitors targeting Chikungunya Virus nsP3 macrodomain by fragment-based drug design

  • PLoS One. 2021 Jan 22;16(1):e0245013. doi: 10.1371/journal.pone.0245013.
Sixue Zhang 1,  Atefeh Garzan 1,  Nicole Haese 2,  Robert Bostwick 3,  Yohanka Martinez-Gzegozewska 3,  Lynn Rasmussen 3,  Daniel N Streblow 2,  Mark T Haise 4,  Ashish K Pathak 1,  Corinne E Augelli-Szafran 1,  Mousheng Wu 1
Affiliations

Affiliations

  • 1 Drug Discovery Division, Chemistry Department, Southern Research, Birmingham, Alabama, United States of America.
  • 2 Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America.
  • 3 Drug Discovery Division, High-Throughput Screening Center, Southern Research, Birmingham, Alabama, United States of America.
  • 4 Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
PMID: 33482665 DOI: 10.1371/journal.pone.0245013
Abstract

The macrodomain of nsP3 (nsP3MD) is highly conserved among the alphaviruses and ADP-ribosylhydrolase activity of Chikungunya Virus (CHIKV) nsP3MD is critical for CHIKV viral replication and virulence. No small molecule drugs targeting CHIKV nsP3 have been identified to date. Here we report small fragments that bind to nsP3MD which were discovered by virtually screening a fragment library and X-ray crystallography. These identified fragments share a similar scaffold, 2-pyrimidone-4-carboxylic acid, and are specifically bound to the ADP-ribose binding site of nsP3MD. Among the fragments, 2-oxo-5,6-benzopyrimidine-4-carboxylic acid showed anti-CHIKV activity with an IC50 of 23 μM. Our fragment-based drug discovery approach provides valuable information to further develop a specific and potent nsP3 inhibitor of CHIKV viral replication based on the 2-pyrimidone-4-carboxylic acid scaffold. In silico studies suggest this pyrimidone scaffold could also bind to the macrodomains of other alphaviruses and coronaviruses and thus, have potential pan-antiviral activity.

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