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A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution

By Zhihua Ou, Christos Ouzounis, Daxi Wang, Wanying Sun, Junhua Li, Weijun Chen, Philippe Marlière, Antoine Danchin

Posted 21 Jun 2020
bioRxiv DOI: 10.1101/2020.06.20.162933 (published DOI: 10.1093/gbe/evaa229)

Fighting the COVID-19 epidemic summons deep understanding of the way SARS-CoV-2 taps into its host cell metabolic resources. We describe here the singular metabolic background that creates a bottleneck constraining coronaviruses to evolve towards likely attenuation in the long term. Cytidine triphosphate (CTP) is at the crossroad of the biosynthetic processes that allow the virus to multiply. This is because CTP is in demand for three essential steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope and, finally, it is a critical building block of the host transfer RNAs synthesis. The CCA 3'-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. We also highlight and provide a raison d'etre to viperin, an enzyme of innate antiviral immunity, which synthesizes 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) as an extremely efficient antiviral nucleotide. ### Competing Interest Statement AD is a founder of Stellate Therapeutics, a company developing applications of metabolism for prevention and cure of neurodegenerative diseases and a founder of Virtexx, a company developing antiviral molecules. ZO and authors from Shenzhen are employed by the BGI, a company developing applications of genome studies. PM is a founder of Theraxen, a company developing synthetic biology approaches for drug development. The other authors declare no conflict of interest.

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