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SARS-CoV-2 ORF8 dimerization and binding mode analysis with class I MHC: computational approaches to identify COVID-19 inhibitors
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SYSNO ASEP 0570494 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title SARS-CoV-2 ORF8 dimerization and binding mode analysis with class I MHC: computational approaches to identify COVID-19 inhibitors Author(s) Selvaraj, C. (IN)
Dinesh, Dhurvas Chandrasekaran (UOCHB-X) ORCID
Pedone, E. M. (IT)
Alothaim, A. S. (SA)
Vijayakumar, R. (SA)
Rudhra, O. (IN)
Singh, S. K. (IN)Source Title Briefings in Functional Genomics - ISSN 2041-2649
Roč. 22, č. 2 (2023), s. 227-240Number of pages 14 s. Language eng - English Country GB - United Kingdom Keywords SARS-CoV-2 ; ORF8 ; SARS-CoV ; dimer ; disulfide bond ; covid-19 ; protein-protein interactions ; molecular dynamics ; MHC-1 ; immune evasion ; viral peptides OECD category Biochemistry and molecular biology Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000938832300001 EID SCOPUS 85152604947 DOI 10.1093/bfgp/elac046 Annotation SARS-CoV-2 encodes eight accessory proteins, one of which, ORF8, has a poorly conserved sequence with SARS-CoV and its role in viral pathogenicity has recently been identified. ORF8 in SARS-CoV-2 has a unique functional feature that allows it to form a dimer structure linked by a disulfide bridge between Cys20 and Cys20 (S-S). This study provides structural characterization of natural mutant variants as well as the identification of potential drug candidates capable of binding directly to the interchain disulfide bridge. The lead compounds reported in this work have a tendency to settle in the dimeric interfaces by direct interaction with the disulfide bridge. These molecules may disturb the dimer formation and may have an inhibition impact on its potential functional role in host immune evasion and virulence pathogenicity. This work provides detailed insights on the sequence and structural variability through computational mutational studies, as well as potent drug candidates with the ability to interrupt the intermolecular disulfide bridge formed between Cys20 and Cys20. Furthermore, the interactions of ORF8 peptides complexed with MHC-1 is studied, and the binding mode reveals that certain ORF8 peptides bind to MHC-1 in a manner similar to other viral peptides. Overall, this study is a narrative of various computational approaches used to provide detailed structural insights into SARS-CoV-2 ORF8 interchain disulfide bond disruptors. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1093/bfgp/elac046
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