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.

中文翻译：

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SARS-CoV-2 偶联逃避对活化核苷酸合成的炎症反应

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 在宿主免疫的压力下迅速进化，尽管接种了有效的疫苗，但新出现的变异浪潮证明了这一点，这凸显了补充抗病毒药物的必要性。我们报告说，靶向嘧啶合成酶可恢复炎症反应并耗尽核苷酸库以阻止 SARS-CoV-2 感染。SARS-CoV-2 使用 Nsp9 来激活氨甲酰磷酸合成酶、天冬氨酸转氨甲酰酶和二氢乳清酶 (CAD)，后者催化从头合成嘧啶的限速步骤。激活的 CAD 不仅促进从头合成核苷酸，而且还使 RelA 脱酰胺。虽然 RelA 脱酰胺会关闭 NF-κB 激活和随后的炎症反应，它上调关键的糖酵解酶以促进有氧糖酵解，为从头合成核苷酸提供代谢物。一种新合成的 CAD 小分子抑制剂可恢复抗病毒炎症反应并耗尽嘧啶池，从而有效地阻止 SARS-CoV-2 复制。因此，针对一种必需的细胞代谢酶提供了一种抗病毒策略，该策略对 SARS-CoV-2 基因变化更难控制。