Comparative analysis of SARS-CoV-2 envelope viroporin mutations from COVID-19 deceased and surviving patients revealed implications on its ion-channel activities and correlation with patient mortality

Abstract

One major obstacle in designing a successful therapeutic regimen to combat COVID-19 pandemic is the frequent occurrence of mutations in the SARS-CoV-2 resulting in patient to patient variations. Out of the four structural proteins of SARS-CoV-2 namely, spike, envelope, nucleocapsid and membrane, envelope protein governs the virus pathogenicity and induction of acute-respiratory-distress-syndrome which is the major cause of death in COVID-19 patients. These effects are facilitated by the viroporin (ion-channel) like activities of the envelope protein. Our current work reports metagenomic analysis of envelope protein at the amino acid sequence level through mining all the available SARS-CoV-2 genomes from the GISAID and coronapp servers. We found majority of mutations in envelope protein were localized at or near PDZ binding motif. Our analysis also demonstrates that the acquired mutations might have important implications on its structure and ion-channel activity. A statistical correlation between specific mutations (e.g. F4F, R69I, P71L, L73F) with patient mortalities were also observed, based on the patient data available for 18,691 SARS-CoV-2-genomes in the GISAID database till 30 April 2021. Albeit, whether these mutations exist as the cause or the effect of co-infections and/or co-morbid disorders within COVID-19 patients is still unclear. Moreover, most of the current vaccine and therapeutic interventions are revolving around spike protein. However, emphasizing on envelope protein’s (1) conserved epitopes, (2) pathogenicity attenuating mutations, and (3) mutations present in the deceased patients, as reported in our present study, new directions to the ongoing efforts of therapeutic developments against COVID-19 can be achieved by targeting envelope viroporin.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• COVID-19
• envelope protein
• viroporin
• ion-channel
• mutations correlated with mortalities

Acknowledgements

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. V. Singh and R. Shobhawat acknowledge their CSIR-NET research fellowships. V. Sharma is grateful to Dr. Saroj Kumar, AIIMS for his mentorship and support. V. Singh also acknowledges Dr. Kausik, IGIB, New Delhi; AK and SK acknowledge Dr. Bhabatosh Das, Centre for Human Microbial Ecology, THSTI, Faridabad for their immense support for the current work. All authors express their sincere gratitude to their parents, family, friends, teachers and the almighty God for their continuous encouragement and support to complete this study. All authors approved the manuscript. We also acknowledge the use of Chimera (https://www.cgl.ucsf.edu/chimera/)for preparing some of the figures in this work. SKD acknowledges Dr. B.R. Ambedkar Center for Biomedical Research (ACBR) and the University of Delhi for various supports to complete this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contribution

SKD, HM, TR and AK conceptualized the study, developed methodologies to analyze metagenomic and other data. SKD, TR, AK, HM, V. Sharma, V. Singh, SK, R. Shobhawat, MP, JKD and HS processed the data and conducted the analysis of results. SKD, TR, AK, V. Sharma, V. Singh and R. Shobhawat analyzed the mutations, while HMG and TR along with all others prepared the final tables for all mutations. R. Saini and HKV performed the statistical analysis of mutations and plotted relevant graph. RS R. Shobhawat built and validated the E protein full-length model. SKD, TR, AK, and V. Sharma drafted the manuscript while others helped in proof-reading.