SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.
Proc Natl Acad Sci U S A
; 119(26): e2122897119, 2022 06 28.
Article
in English
| MEDLINE | ID: covidwho-1890411
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
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Pyrimidines
/
Aspartate Carbamoyltransferase
/
Virus Replication
/
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)
/
Dihydroorotase
/
Enzyme Inhibitors
/
SARS-CoV-2
/
COVID-19 Drug Treatment
Topics:
Vaccines
/
Variants
Limits:
Animals
/
Humans
Language:
English
Journal:
Proc Natl Acad Sci U S A
Year:
2022
Document Type:
Article
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