AUTHOR=Assadizadeh Mohammad , Azimzadeh Irani Maryam 

TITLE=Oligomer formation of SARS-CoV-2 ORF8 through 73YIDI76 motifs regulates immune response and non-infusion antiviral interactions

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1270511

DOI=10.3389/fmolb.2023.1270511

ISSN=2296-889X

ABSTRACT=<p><bold>Introduction:</bold> Open Reading Frame 8 (ORF8) is a 121 amino acid length SARS-CoV-2 specific accessory protein that plays crucial roles in viral infectivity, and pathogenesis. Current SARS-CoV-2 treatments focus on spike or RNA-dependent RNA polymerase proteins. Hence, directing attention to ORF8 yields substantial benefits for innovative non-infusional therapeutics. Functional ORF8 is proposed to form oligomers via a crystallographic contact centered by 73YIDI76 motifs.</p><p><bold>Methods:</bold> Hence, the structure and atomistic interactions of trimeric and tetrameric ORF8 oligomeric forms were modeled by means of thorough molecular modeling and molecular dynamics simulations.</p><p><bold>Results:</bold> Results show that trimeric and tetrameric oligomers are stabilized by the interaction of β4-β5 (47-83) loops. 73YIDI76 motifs are involved in obtaining the oligomerization interfaces. It is shown that the tetramers which resemble a doughnut-like construction are the most stabilized oligomeric forms. Where four β4-β5 loops form the interfaces between two dimers. Each monomer links to two others through β4-β5 loops and a covalent Cys20-Cys20 bridge. Epitope mapping, binding site predictions, and solvent-accessible surface area analyses of different ORF8 forms show that the B-cell, MHC-I, and drug epitopes stay exposed in oligomeric forms.</p><p><bold>Discussion:</bold> Approving that the viral infectivity is expanded upon ORF8 oligomerization and the regions involved in oligomerization can be considered as therapeutic targets.</p>