Identification of evolutionarily stable functional and immunogenic sites across the SARS-CoV-2 proteome and greater coronavirus family.

Chen Wang,Harikumar Govindarajan,Panagiotis Katsonis,Daniel M Konecki,Thomas Bourquard,David C Marciano,Brigitta Wastuwidyaningtyas,Olivier Lichtarge,Amanda M Williams,Alfonso Valencia

doi:10.1093/bioinformatics/btab406

Chen Wang, Harikumar Govindarajan + Show 8 more

Open Access

https://doi.org/10.1093/bioinformatics/btab406

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Abstract

MotivationSince the first recognized case of COVID-19, more than 100 million people have been infected worldwide. Global efforts in drug and vaccine development to fight the disease have yielded vaccines and drug candidates to cure COVID-19. However, the spread of SARS-CoV-2 variants threatens the continued efficacy of these treatments. In order to address this, we interrogate the evolutionary history of the entire SARS-CoV-2 proteome to identify evolutionarily conserved functional sites that can inform the search for treatments with broader coverage across the coronavirus family.ResultsCombining coronavirus family sequence information with the mutations observed in the current COVID-19 outbreak, we systematically and comprehensively define evolutionarily stable sites that may provide useful drug and vaccine targets and which are less likely to be compromised by the emergence of new virus strains. Several experimentally validated effective drugs interact with these proposed target sites. In addition, the same evolutionary information can prioritize cross reactive antigens that are useful in directing multi-epitope vaccine strategies to illicit broadly neutralizing immune responses to the betacoronavirus family. Although the results are focused on SARS-CoV-2, these approaches stem from evolutionary principles that are agnostic to the organism or infective agent.Availability and implementationThe results of this work are made interactively available at http://cov.lichtargelab.org.Supplementary information Supplementary data are available at Bioinformatics online.

Highlights

Statement By examining past evolutionary pressures in the coronavirus family and in the present SARSCoV-2 outbreak, we identified functional sites in the SARS-CoV-2 proteome that are not affected by variants in the current outbreak
For the proteins that do not reach significant z-scores there is a clear correlation to a lack of sequences in the alignments (e.g. NSP1, E, ORF3, and ORF7a), or, the structure belongs to a small domain within a larger protein
This study was motivated by the current pandemic and uses evolutionary sequence information to guide the development of therapeutics for COVID-19

Summary

Introduction

Finding ways to control and prevent further infection are top priorities which include the targeted discovery of drugs that impair viral mechanisms (Youngchang Kim et al, 2020; Li et al, 2020; Rut et al, 2020) and antigenic epitopes through which vaccines raise immunity (Mullard, 2020; Poh et al, 2020; van Doremalen et al, 2020). This study addresses both by utilizing evolutionary information from SARS-CoV-2 sequence and structural data to search for actionable functional sites for each protein in the SARS-CoV-2 genome

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