Thesis (Ph.D)-Cairo University, 2023.

Bibliography: pages 76-90.

Background: Terpenoids from the chaga mushroom have been identified as potential antiviral agents against SARS-CoV-2. This is because it can firmly bind to the viral spike receptor binding domain (RBD) and the auxiliary host cell receptor glucose-regulated protein 78 (GRP78). The current work examines the association of the chaga mushroom terpenoids with RBD of various SARS-CoV-2 variants, including alpha, beta, gamma, delta, and omicron. This association was compared to the SARS-CoV-2 wildtype (WT) RBD. The outcomes demonstrated that the mutant RBDs, which had marginally greater average binding affinities (better binding) than the WT, were successfully inhibited by the chaga mushroom terpenoids. The results suggests that the chaga mushroom can be effective against various SARS-CoV-2 variants by targeting both the host-cell surface receptor GRP78 and the viral spike RBD. The bacterium Lactococcus lactis produces the polycyclic antimicrobial peptide nisin, which is utilized as a food preservative. The unusual amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha), and didehydroaminobutyric acid (Dhb) are among its 34 amino acid residues. Pep42 is a cyclic peptide of length 13 amino acids CTVALPGGYVRVC. The present study investigates the binding of both peptides to the host cell receptor, glucose-regulated protein 78 (GRP78). The results showed that pep42 has a higher binding affinity than NisinA. According to the findings, cyclic peptides can block GRP78 more effectively than NisinA.
Material and Methods: In this thesis, Using a blind docking using AutoDock Tools, the bound ligand and all crystallographic water molecules were removed from the 3D structure. At the RBD, various mutations were applied to the structures to make them resemble the many spike protein variants, including the alpha, beta, gamma, delta, and omicron. After that, molecular dynamics simulation was implemented to relax the models for 100 ns. Cluster analysis was then performed on the trajectories where representative frames are used in the docking study. Nisin and PEP42's binding process utilized AutoDock Tools' blind docking technique, following that a 100ns molecular dynamics simulation was run.
Results: The binding affinities of the chaga terpenoids in the mutated RBDs show significantly higher values than in the WT RBD. Inonotusol F shows the best choice for all examined RBD variants, as WT had predicted average binding affinities ranging from -7.9 to -8.4 kcal/mol. Moreover, cyclic peptide pep42 is associated with host cell receptor GRP78 with a higher affinity (-7.6 kcal/mol) than NisinA (-6.7 kcal/mol).

Conclusion: Chaga mushroom as a potential natural antiviral against SARS-CoV-2 and its different variants. The development of natural antiviral treatments can significantly enhance the drug therapeutic pipeline against COVID-19. Furthermore, cyclic peptide pep42 may be a more effective inhibitor of GRP78 than nisin. It can stop a lot of diseases from getting inside the cell.

تم تحديد التربينويدات من فطر تشاجا كعوامل محتملة مضادة للفيروسات ضد السارس- CoV-2. هذا لأنه يمكن أن يرتبط بقوة بمجال ربط مستقبلات السنبلة الفيروسية (RBD) وبروتين الجلوكوز المنظم لمستقبل الخلية المضيفة المساعدة 78 (GRP78). يدرس العمل الحالي ارتباط تربينيدات فطر تشاجا مع RBD لمختلف متغيرات SARS-CoV-2 ، بما في ذلك alpha و beta و gamma و delta و omicron. تمت مقارنة هذا الارتباط مع SARS-CoV-2 wildtype (WT) RBD باستخدام تحليل الالتحام الجزيئي ونمذجة الديناميات الجزيئية. أظهرت النتائج أن RBDs الطافرة ، التي كان لها ارتباطات ارتباط متوسط أكبر بشكل هامشي (ارتباط أفضل) من WT ، تم تثبيتها بنجاح بواسطة تربينويد فطر تشاجا. تشير النتائج إلى أن فطر تشاجا يمكن أن يكون فعالًا ضد متغيرات SARS-CoV-2 المختلفة من خلال استهداف كل من مستقبلات سطح الخلية المضيفة GRP78 والارتفاع الفيروسي RBD.

Issues also as CD.

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