Section of Infection and Immunity, Herman Ostrow School of Dentistry, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089.
Department of Chemistry, Dornsife College of Arts, Letters and Sciences, University of Southern California, Los Angeles, CA 90089.
Proc Natl Acad Sci U S A. 2022 Jun 28;119(26):e2122897119. doi: 10.1073/pnas.2122897119. Epub 2022 Jun 14.
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.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）在宿主免疫压力下迅速进化，尽管有有效的疫苗接种，但新兴变种仍层出不穷，这凸显了需要补充抗病毒药物的必要性。我们报告称，靶向嘧啶合成酶可恢复炎症反应并耗尽核苷酸池，从而阻止 SARS-CoV-2 感染。SARS-CoV-2 部署 Nsp9 激活氨甲酰磷酸合成酶、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD），这些酶催化从头嘧啶合成的限速步骤。激活的 CAD 不仅为从头核苷酸合成提供燃料，还使 RelA 脱酰胺化。虽然 RelA 脱酰胺作用会关闭 NF-κB 激活和随后的炎症反应，但它会上调关键的糖酵解酶，以促进有氧糖酵解，为从头核苷酸合成提供代谢物。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，从而有效阻止 SARS-CoV-2 复制。因此，靶向必需的细胞代谢酶提供了一种抗病毒策略，这种策略对 SARS-CoV-2 的遗传变化更具抗性。
