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.
Artículo
en Inglés
| 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.
Palabras clave
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Pirimidinas
/
Aspartato Carbamoiltransferasa
/
Replicación Viral
/
Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)
/
Dihidroorotasa
/
Inhibidores Enzimáticos
/
SARS-CoV-2
/
Tratamiento Farmacológico de COVID-19
Tópicos:
Vacunas
/
Variantes
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
Proc Natl Acad Sci U S A
Año:
2022
Tipo del documento:
Artículo
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