Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8
Mostafa Bagheri-Far, Mohammad Assadizadeh, Maryam Azimzadeh-Irani, Mohammad Yaghoubi-Avini, Seyed Massoud Hosseini
doi:10.22099/mbrc.2024.50245.2001
The recent pernicious COVID-19 pandemic is caused by SARS-CoV-2. While most therapeutic strategies have focused on the viral spike protein, Open Reading Frame 8 (ORF8) plays a critical role in causing the severity of the disease. Nonetheless, there still needs to be more information on the ORF8 binding epitopes and their appropriate safe inhibitors. Herein, the protein binding sites were detected through comprehensive structural analyses. The validation of the binding sites was investigated through protein conservation analysis and blind docking. The potential natural product (NP) inhibitors were selected based on a structurefunction approach. The solo and combined inhibition functions of these NPs were examined through molecular docking studies. Two binding epitopes were identified, one between the ORF8 monomers (DGBM) and the other on the surface (Gal1-Like). E92 was predicted to be pivotal for DGBM, and R101 for Gal1-like, which was then confirmed through molecular dockings. The inhibitory effects of selected phytochemical (Artemisinin), bacterial (Ivermectin), and native-liken (DEG-168) NPs were compared with the Remdesivir. Selected NPs showed solo-and co-functionality against Remdesivir to inhibit functional regions of the ORF8 structure. The DGBM is highly engaged in capturing the NPs. Additionally, the co-functionality study of NPs showed that the Ivermectin-DEG168 combination has the strongest mechanism for inhibiting all the predicted binding sites. Ivermectin can interfere with ORF8-MHC-I interaction through inhibition of A51 and F120. Two new binding sites on this non-infusion protein structure were introduced using a combination of approaches. Additionally, three safe and effective were found to inhibit these binding sites.
Conflict of Interest: The authors have no relevant financial or non-financial interests to disclose. Authors' Contribution: MBF carried out the analyses and provided all figures and tables and wrote the initial draft. MA re-wrote the manuscript text and citations and revised the manuscript. MAI designed and supervised the project, edited the text, figures and plots, interpreted the data and outlined the manuscript. SMH contributed in interpretation of the results and co-supervised the project. MYA contributed in interpretation of the results.
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'title': 'Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein '
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