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

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.

Keywords: COVID-19; COVID-19 therapeutics; ORF8; SARS-CoV-2; structural biology.

FIGURE 1

SARS-CoV-2 ORF8 protein interaction map. ORF8 modulates vesicular traffic through the unfolded protein response (UPR) and, therefore, ER stress by stimulating the ATF6 and IRE1 pathways through the upregulation of the GRP78 and GRP94 chaperones. Likewise, this process is linked to other intracellular interactions in the nucleus, Golgi apparatus, cytoskeleton, mitochondria, cytoplasm, and membrane. Rapamycin (Sirolimus) could indirectly decrease the effects of ORF8 by blocking FKBP7 and FKBP10 but not PERK pathway. Created with BioRender.com.