Biochemical and mathematical lessons from the evolution of the SARS-CoV-2 virus: paths for novel antiviral warfare

Abstract

In the fight against the spread of COVID-19 the emphasis is on vaccination or on reactivating existing drugs used for other purposes. The tight links that necessarily exist between the virus as it multiplies and the metabolism of its host are systematically ignored. Here we show that the metabolism of all cells is coordinated by the availability of a core building block of the cell’s genome, cytidine triphosphate (CTP). This metabolite is also the key to the synthesis of the viral envelope and to the translation of its genome into proteins. This unique role explains why evolution has led to the early emergence in animals of an antiviral immunity enzyme, viperin, that synthesizes a toxic analogue of CTP. The constraints arising from this dependency guide the evolution of the virus. With this in mind, we explored the real-time experiment taking place before our eyes using probabilistic modelling approaches to the molecular evolution of the virus. We have thus followed, almost on a daily basis, the evolution of the composition of the viral genome to link it to the progeny produced over time, particularly in the form of blooms that sparked a firework of viral mutations. Some of those certainly increase the propagation of the virus. This led us to make out the critical role in this evolution of several proteins of the virus, such as its nucleocapsid N, and more generally to begin to understand how the virus ties up the host metabolism to its own benefit. A way for the virus to escape CTP-dependent control in cells would be to infect cells that are not expected to grow, such as neurons. This may account for unexpected body sites of viral development in the present epidemic.

Emerging SARS‐CoV‐2 variants can potentially break set epidemiological barriers in COVID‐19

“…Moreover, how the new mutations in the emerging variants are affecting the host-cell metabolism, will greatly affect their success in gaining the entry and multiplication inside the cells. 65 This also requires to be explored in-depth to understand the evolving host-virus interactions in the emerging variants.…”

SARS‐CoV‐2 biology and variants: anticipation of viral evolution and what needs to be done

“…Many mutations in this protein elevate the mutation load of the virus (Eskier et al ., 2020). Scrutiny of mutations in this bifunctional enzyme has already revealed formation of ‘blooms’ of novel viral lineages, some of which are likely to result in attenuation (Cluzel et al ., 2020).…”

“…It is therefore expected that coronaviruses have evolved defences that alleviate the burden of this chemical assault. Monitoring consistent changes in the number of transversions in specific lineages of the virus is, therefore, of great importance (Cluzel et al ., 2020).…”

Non-uniform aspects of the SARS-CoV-2 intraspecies evolution reopen question of its origin

“…In the context of the origin of SARS-CoV-2, cytidine triphosphate (CTP) plays an important role in the synthesis of the precursors of the viral envelope and protein glycosylation, which has allowed to link mutational studies to the timelines [125] . The essential function of CTP in the synthesis of the viral envelope and the translation of its genome has led to the emergence of a toxic CTP analogue synthesized by viperin possessing antiviral immunogenicity [126] . Application of a probabilistic modelling approach for investigation of the molecular evolution of the virus has allowed real-time monitoring on a daily basis.…”