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Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8

Bagheri-Far et al., Molecular Biology Research Communications, doi:10.22099/mbrc.2024.50245.2001
Oct 2024  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 110 treatments. c19ivm.org
In Silico study showing that ivermectin, artemisinin, and DEG-168 may inhibit SARS-CoV-2 by targeting the ORF8 protein's binding sites. Ivermectin showed the highest binding affinity. Authors identified two key binding regions on ORF8 - a deep groove between monomers (DGBM) and a galectin-1-like site. Docking studies found the natural products, especially in combination, effectively bound these sites with high affinity. Inhibiting ORF8 could reduce SARS-CoV-2's immune evasion and pathogenic functions.
70 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N768, Dengue34,69,70, HIV-170, Simian virus 4071, Zika34,72,73, West Nile73, Yellow Fever74,75, Japanese encephalitis74, Chikungunya75, Semliki Forest virus75, Human papillomavirus54, Epstein-Barr54, BK Polyomavirus76, and Sindbis virus75.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins68,70,71,77, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing35, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination38,78, shows dose-dependent inhibition of wildtype and omicron variants33, exhibits dose-dependent inhibition of lung injury58,63, may inhibit SARS-CoV-2 via IMPase inhibition34, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation7, inhibits SARS-CoV-2 3CLpro51, may inhibit SARS-CoV-2 RdRp activity26, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages57, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation79, may interfere with SARS-CoV-2's immune evasion via ORF8 binding2, may inhibit SARS-CoV-2 by disrupting CD147 interaction80-83, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1956,84, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage6, may minimize SARS-CoV-2 induced cardiac damage37,45, increases Bifidobacteria which play a key role in the immune system85, has immunomodulatory48 and anti-inflammatory67,86 properties, and has an extensive and very positive safety profile87.
Bagheri-Far et al., 26 Oct 2024, peer-reviewed, 5 authors. Contact: m_azimzadeh@sbu.ac.ir, ma_hosseini@sbu.ac.ir.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
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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