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Sci Rep ; 12(1): 14972, 2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-2028722


During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to-U mutation, suggesting a potential mutational role by host APOBEC cytosine deaminases that possess broad anti-viral activity. We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations. However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs. Instead, expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the random mutations, this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure.

COVID-19 , RNA Editing , APOBEC Deaminases/genetics , APOBEC Deaminases/metabolism , COVID-19/genetics , Caco-2 Cells , Cytidine Deaminase , Humans , Mutation , Pandemics , Proteins , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics
Proc Natl Acad Sci U S A ; 119(26): e2122897119, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1890411


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.

Antiviral Agents , Aspartate Carbamoyltransferase , COVID-19 Drug Treatment , Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) , Dihydroorotase , Enzyme Inhibitors , Pyrimidines , SARS-CoV-2 , Virus Replication , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Aspartate Carbamoyltransferase/antagonists & inhibitors , Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/antagonists & inhibitors , Dihydroorotase/antagonists & inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Inflammation/drug therapy , Mice , Pyrimidines/antagonists & inhibitors , Pyrimidines/biosynthesis , RNA-Binding Proteins/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Transcription Factor RelA/metabolism , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects