tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2022 Jun 28;119(26):e2122897119.
doi: 10.1073/pnas.2122897119. Epub 2022 Jun 14.
SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis
Chao Qin[SUP] 1 [/SUP], Youliang Rao[SUP] 1 [/SUP], Hao Yuan[SUP] 1 2 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Jun Zhao[SUP] 1 3 [/SUP], Bianca Espinosa[SUP] 2 [/SUP], Yongzhen Liu[SUP] 1 [/SUP], Shu Zhang[SUP] 1 [/SUP], Ali Can Savas[SUP] 1 [/SUP], Qizhi Liu[SUP] 1 [/SUP], Mehrnaz Zarinfar[SUP] 1 [/SUP], Stephanie Rice[SUP] 1 [/SUP], Jill Henley[SUP] 4 [/SUP], Lucio Comai[SUP] 4 [/SUP], Nicholas A Graham[SUP] 5 [/SUP], Casey Chen[SUP] 1 [/SUP], Chao Zhang[SUP] 2 [/SUP], Pinghui Feng[SUP] 1 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
Keywords: CAD; SARS-CoV-2; deamidation; inflammatory response; metabolism.
. 2022 Jun 28;119(26):e2122897119.
doi: 10.1073/pnas.2122897119. Epub 2022 Jun 14.
SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis
Chao Qin[SUP] 1 [/SUP], Youliang Rao[SUP] 1 [/SUP], Hao Yuan[SUP] 1 2 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Jun Zhao[SUP] 1 3 [/SUP], Bianca Espinosa[SUP] 2 [/SUP], Yongzhen Liu[SUP] 1 [/SUP], Shu Zhang[SUP] 1 [/SUP], Ali Can Savas[SUP] 1 [/SUP], Qizhi Liu[SUP] 1 [/SUP], Mehrnaz Zarinfar[SUP] 1 [/SUP], Stephanie Rice[SUP] 1 [/SUP], Jill Henley[SUP] 4 [/SUP], Lucio Comai[SUP] 4 [/SUP], Nicholas A Graham[SUP] 5 [/SUP], Casey Chen[SUP] 1 [/SUP], Chao Zhang[SUP] 2 [/SUP], Pinghui Feng[SUP] 1 [/SUP]
Affiliations
- PMID: 35700355
- DOI: 10.1073/pnas.2122897119
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
Keywords: CAD; SARS-CoV-2; deamidation; inflammatory response; metabolism.