Functional pangenome analysis suggests inhibition of the protein E as a readily available therapy for COVID-2019

Abstract

The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells 1 . The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar 2 , but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-2 3 . Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS) 4-6 , the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection 7,8 . However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride 9,10 ) or the PBM (SB203580 5 ), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.

Understanding genomic diversity, pan-genome, and evolution of SARS-CoV-2

“…A total of 44 protein-coding region clusters represent the pan-genome of nineteen studied genus Betacoronavirus members amongst which, 3 protein-coding regions (S, M and N proteins) were found to be conserved across all genomes, representing the core genome. A similar analysis has been performed on all Betacoronavirus species; however, it does not include Pangolin CoV (Alam et al, 2020). Our study also recognized that the pan-genome of genus Betacoronavirus is open, which means that with the addition of a new species, the pan-genome is continuously increasing (Fig.…”

Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19

“…210 Another hypothesis is that this protein, if not an artifact, could be involved with regulating molecular function or contributing to response stimulus based on DeepGOPlus Gene Ontology. 211 In another study, based on the SARS-CoV-2 interactome, ORF10 is suggested to interact with a Cullin 2 RING E3 ligase complex. 204 Potentially, ORF10 might bind specifically to Cullin 2 ZYG11B complex and hijack this complex for ubiquitination and degradation.…”

“…It appears to localize only within the extracellular region of the host. 211 Structural analysis of SARS-CoV-2 ORF10 -ORF10 of SARS-CoV-2 is the last predicted coding sequence upstream of the poly-A tail and is the shortest predicted coding sequence, composed of 38 a.a. 210 ORF10 is predicted to harbor a long helix and a pair of ϐ-strands. ORF10 is not found within the SARS-CoV-1 proteome.…”

Therapeutic approaches for COVID 19: Challenges and successes

“…[8] When the S protein binds to Angiotensin II type 1 (AT1) receptors, it results in over-activation of the ACE-AngII-AT1 pathway which has shown to induce inflammatory responses and possibly fibrosis of the lungs or other organs [9]. The logical approach to the therapy is to combat this interaction, thus the S protein presents a prime target for potential vaccines [10]. An article published on 17 March 2020 suggested the use of Losartan (ACE2 antagonist) as a potential protective barrier against the lung damage generated by COVID-19 infection [9].…”