Structural Analysis of SARS-CoV-2 ORF8 Protein: Pathogenic and Therapeutic Implications

Antonio Valcarcel,Elena R Álvarez-Buylla,José Díaz,Antonio Bensussen

doi:10.3389/fgene.2021.693227

Abstract

Current therapeutic strategies and vaccines against SARS-CoV-2 are mainly focused on the Spike protein despite there are other viral proteins with important roles in COVID-19 pathogenicity. For example, ORF8 restructures vesicular trafficking in the host cell, impacts intracellular immunity through the IFN-I signaling, and growth pathways through the mitogen-activated protein kinases (MAPKs). In this mini-review, we analyze the main structural similarities of ORF8 with immunological molecules such as IL−1, contributing to the immunological deregulation observed in COVID-19. We also propose that the blockage of some effector functions of ORF8 with Rapamycin, such as the mTORC1 activation through MAPKs 40 pathway, with Rapamycin, can be a promising approach to reduce COVID-19 mortality.

Highlights

The SARS-CoV-2 appeared in Wuhan at the end of December 2019 with the consequent crisis in the health systems due to the lack of an effective treatment to face a unknown disease with a mortality of 10%
The work of Mullen et al (2021) provide evidence of mTORC1 activation in lung tissue from COVID-19 patients, and that mTORC1 inhibitors reduce viral replication in renal epithelial cells and lung airfluid interface (ALI) cultures. These results suggest that targeting mTORC1 can be a feasible treatment strategy for COVID19 patients, more studies are required to determine the mechanism of inhibition and potential efficacy in patients
ORF8 is the most linked protein in the virus-host hybrid molecular network formed during the SARS-CoV-2 infection

Summary

INTRODUCTION

The SARS-CoV-2 appeared in Wuhan at the end of December 2019 with the consequent crisis in the health systems due to the lack of an effective treatment to face a unknown disease with a mortality of 10%. The search for direct inhibition drugs of ORF8 is difficult due to the globular structure and high variability of this viral component Another distinct function of ORF8 protein, different form SARS-CoV 29 nucleotide deleted versions- ORF8a and ORF8b (Pereira, 2021), is the regulation of the amount of MHC-I on the surface of the infected cell through a mechanism of lysosomal degradation dependent on autophagy. The joint action of ORF8, Nsp, and Nsp results in a significant decrease in the production of IFN-I through different mechanisms to suppress signaling and produce failures and incorrect immune response, which favors the replication and transmission of the virus, to other host cells (Xia et al, 2020) Another example of this synergy is Nsp, Nsp, ORF3b, and M that can act together with ORF8 in more than one cell organelle, as in the case of stress-induced to ER (Figure 1; Gordon et al, 2020). Incomplete stimulation produces anergy (Rollins and Gibbons, 2017), which may be used by SARS-CoV-2 to enhance its replication

Findings

DISCUSSION

CONCLUSION