Targeted Molecular Screening of Fungal Metabolites for Blocking Rabies lyssavirus Infection Mechanisms
Abstract
Background: Rabies is a fatal virus that spreads to humans through the saliva of infected animals, typically via bites. With limited options for treatment at present, Rabies lyssavirus (RABV) remains a serious public health concern. In order to find potential antiviral possibilities, the study aimed to examine the in-silico interactions between fungal metabolites and important RABV proteins, including RABV-G, RABV-L, RABV-P, and RABV-M. After fifty-two (52) metabolites were subjected to molecular docking tests, eighteen (18) fungal metabolites were selected for further physicochemical and pharmacokinetic evaluation. Significantly, the Chaetoglobosin A and Cladospirone B both showed encouraging interactions with RABV-G and RABV-L. Moreover, the data showed that Chaetoglobosin C had the best binding affinity with both proteins. Furthermore, the majority of drugs' ADMET profiles showed positive pharmacokinetic characteristics. However, improving blood-brain barrier (BBB) permeability and increasing bioavailability are essential for the advancement of these drugs. Based on the findings, fungal metabolites- particularly Chaetoglobosin C, have considerable amounts of potential as antiviral drugs against the Rabies lyssavirus. Additional in vitro and in vivo testing needs to be performed to assess the success of their use as treatment.
Keywords:
Antiviral Drugs, Chaetoglobosin C, Fungal Metabolites, Rabies lyssavirus
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References
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Desantis, F., Miotto, M., Di Rienzo, L., Milanetti, E., & Ruocco, G. (2022). Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity. Scientific Reports, 12(1), 12087. https://doi.org/10.1038/s41598-022-16338-5
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Kouba, T., Drncova, P., & Cusack, S. (2019). Structural snapshots of actively transcribing influenza polymerase. Nature Structural & Molecular Biology, 26(6), 460-470. https://doi.org/10.1038/s41594-019-0232-z
Lee, M. F., Wu, Y. S., & Poh, C. L. (2023). Molecular mechanisms of antiviral agents against dengue virus. Viruses, 15(3), 705. https://doi.org/10.3390/v15030705
Leeson, P. D., Bento, A. P., Gaulton, A., Hersey, A., Manners, E. J., Radoux, C. J., & Leach, A. R. (2021). Target-based evaluation of “drug-like” properties and ligand efficiencies. Journal of medicinal chemistry, 64(11), 7210-7230. https://doi.org/10.1021/acs.jmedchem.1c00416
Li, G., Du, T., Wang, J., Jie, K., Ren, Z., Zhang, X., ... & Ru, H. (2025). Structural insights into the RNA-dependent RNA polymerase complexes from highly pathogenic Marburg and Ebola viruses. Nature Communications, 16(1), 3080. https://doi.org/10.1038/s41467-025-58308-1
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Ling, M. Y. J., Halim, A. F. N. A., Ahmad, D., Ramly, N., Hassan, M. R., Rahim, S. S. S. A., ... & Hidrus, A. (2023). Rabies in Southeast Asia: a systematic review of its incidence, risk factors and mortality. BMJ Open, 13(5), e066587. https://doi.org/10.1136/bmjopen-2022-066587
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 46(1-3), 3–26. https://doi.org/10.1016/s0169-409x(00)00129-0
Louten, J. (2016). Virus replication. In Essential Human Virology (pp. 49–70). Elsevier. https://doi.org/10.1016/b978-0-12-800947-5.00004-1
Obi, J., Gutiérrez-Barbosa, H., Chua, J., & Deredge, D. (2021). Current trends and limitations in dengue antiviral research. Tropical Medicine and Infectious Disease, 6(4), 180. https://doi.org/10.3390/tropicalmed6040180
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605-1612. https://doi.org/10.1002/jcc.20084
Qaisrani, M. N., Belousov, R., Rehman, J. U., Goliaei, E. M., Girotto, I., Franklin-Mergarejo, R., ... & Roldan, E. (2021). Phospholipids dock SARS-CoV-2 spike protein via hydrophobic interactions: A minimal in-silico study of lecithin nasal spray therapy. The European Physical Journal E, 44(11), 132. https://doi.org/10.1140/epje/s10189-021-00137-3
Quiambao, B., Varghese, L., Demarteau, N., Sengson, R. F., Javier, J., Mukherjee, P., ... & Preiss, S. (2020). Health economic assessment of a rabies pre-exposure prophylaxis program compared with post-exposure prophylaxis alone in high-risk age groups in the Philippines. International Journal of Infectious Diseases, 97, 38-46. https://doi.org/10.1016/j.ijid.2020.05.062
Rampersad, S., & Tennant, P. (2018). Replication and Expression Strategies of Viruses. Viruses, 55–82. https://doi.org/10.1016/b978-0-12-811257-1.00003-6
Rieder, M., Brzózka, K., Pfaller, C. K., Cox, J. H., Stitz, L., & Conzelmann, K. K. (2011). Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity. Journal of virology, 85(2), 842-852. https://doi.org/10.1128/jvi.01427-10
Roy, D., Hinge, V. K., & Kovalenko, A. (2019). To pass or not to pass: predicting the blood–brain barrier permeability with the 3D-RISM-KH molecular solvation theory. ACS Omega, 4(16), 16774-16780. https://doi.org/10.1021/acsomega.9b01512
Salvatore, M. M., Andolfi, A., & Nicoletti, R. (2021). The genus Cladosporium: A rich source of diverse and bioactive natural compounds. Molecules, 26(13), 3959. https://doi.org/10.3390/molecules26133959
Sethi, A., Rawlinson, S. M., Dubey, A., Ang, C. S., Choi, Y. H., Yan, F., ... & Gooley, P. R. (2023). Structural insights into the multifunctionality of rabies virus P3 protein. Proceedings of the National Academy of Sciences, 120(14), e2217066120. https://doi.org/10.1073/pnas.2217066120
Song, X. (2024). Antibacterial, antifungal, and antiviral bioactive compounds from natural products. Molecules, 29(4), 825. https://doi.org/10.3390/molecules29040825
Wang, Z. Z., Shi, X. X., Huang, G. Y., Hao, G. F., & Yang, G. F. (2023). Fragment-based drug discovery supports drugging ‘undruggable’protein–protein interactions. Trends in Biochemical Sciences, 48(6), 539-552. https://doi.org/10.1016/j.tibs.2023.01.008
World Health Organization (2024). Rabies (Fact sheet). https://www.who.int/news-room/fact-sheets/detail/rabies
Yuan, Y., Fang, A., Wang, H., Wang, C., Sui, B., Zhao, J., ... & Zhao, L. (2024). Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism. Mbio, 15(3), e02880-23. https://doi.org/10.1128/mbio.02880-23
Zhan, J., Chakraborty, S., Sethi, A., Mok, Y. F., Yan, F., Moseley, G. W., & Gooley, P. R. (2025). Analysis of mechanisms of the rabies virus P protein-nucleocapsid interaction using engineered N-protein peptides and potential applications in antivirals design. Antiviral Research, 234, 106075. https://doi.org/10.1016/j.antiviral.2024.106075
Zhang, S., Krumberger, M., Morris, M. A., Parrocha, C. M. T., Kreutzer, A. G., & Nowick, J. S. (2021). Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists. European Journal of Medicinal Chemistry, 218, 113390. https://doi.org/10.1016/j.ejmech.2021.113390
Albertini, A. A. V., Schoehn, G., Weissenhorn, W., & Ruigrok, R. W. H. (2008). Structural aspects of rabies virus replication. Cellular and Molecular Life Sciences, 65(2), 282-294. https://doi.org/10.1007/s00018-007-7298-1
Barboro, P., Repaci, E., D’Arrigo, C., & Balbi, C. (2012). The role of nuclear matrix proteins binding to matrix attachment regions (Mars) in prostate cancer cell differentiation. PloS One, 7(7), e40617. https://doi.org/10.1371/journal.pone.0040617
Bornholdt, Z. A., Noda, T., Abelson, D. M., Halfmann, P., Wood, M. R., Kawaoka, Y., & Saphire, E. O. (2013). Structural rearrangement of ebola virus VP40 begets multiple functions in the virus life cycle. Cell, 154(4), 763-774. https://doi.org/10.1016/j.cell.2013.07.015
Bravo-Reyna, C. C., Miranda-Galván, V., Reyes-Soto, G., Vicuña, R., Alanis-Mendizabal, J., Escobar-Valderrama, M., ... & Torres-Villalobos, G. (2024). Evaluation of the Chetomin effect on histopathological features in a murine acute spinal cord injury model. World Neurosurgery: X, 25, 100414. https://doi.org/10.1016/j.wnsx.2024.100414
Carter-Fenk, K., Liu, M., Pujal, L., Loipersberger, M., Tsanai, M., Vernon, R. M., ... & Head-Gordon, T. (2023). The energetic origins of pi–pi contacts in proteins. Journal of the American Chemical Society, 145(45), 24836-24851. https://doi.org/10.1021/jacs.3c09198
Chelbi-Alix, M. K., Vidy, A., Bougrini, J. E., & Blondel, D. (2006). Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. Journal of Interferon & Cytokine Research, 26(5), 271-280. https://doi.org/10.1089/jir.2006.26.271
Chen, J., Zhang, W., Guo, Q., Yu, W., Zhang, Y., & He, B. (2020). Bioactivities and future perspectives of Chaetoglobosins. Evidence‐Based Complementary and Alternative Medicine, 2020(1), 8574084. https://doi.org/10.1155/2020/8574084
Dar, A. M., & Mir, S. (2017). Molecular docking: approaches, types, applications and basic challenges. Journal of Analytical & Bioanalytical Techniques, 8(2), 1-3. https://doi.org/10.4172/2155-9872.1000356
Desantis, F., Miotto, M., Di Rienzo, L., Milanetti, E., & Ruocco, G. (2022). Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity. Scientific Reports, 12(1), 12087. https://doi.org/10.1038/s41598-022-16338-5
Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J. (2014). Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chemistry & Biology, 21(9), 1115-1142. https://doi.org/10.1016/j.chembiol.2014.08.013
Fatima, M., Iqbal, T., Shaheen, L., Salma, U., Siddique, R., Ali, R., ... & Usman, S. (2023). Transmission dynamics of rabies virus. International Journal of Agriculture and Biosciences, 3, 386–397. https://doi.org/10.47278/book.zoon/2023.110
Fisher, C. R., Streicker, D. G., & Schnell, M. J. (2018). The spread and evolution of rabies virus: conquering new frontiers. Nature Reviews Microbiology, 16(4), 241-255. https://doi.org/10.1038/nrmicro.2018.11
Fu, Y., Zhao, J., & Chen, Z. (2018). Insights into the molecular mechanisms of protein‐ligand interactions by molecular docking and molecular dynamics simulation: a case of oligopeptide binding protein. Computational and Mathematical Methods in Medicine, 2018(1), 3502514. https://doi.org/10.1155/2018/3502514
Kimitsuki, K., Khan, S., Kaimori, R., Yahiro, T., Saito, N., Yamada, K., ... & Nishizono, A. (2023). Implications of the antiviral drug favipiravir on rabies immunoglobulin for post-exposure prophylaxis of rabies in mice model with category III-like exposures. Antiviral Research, 209, 105489. https://doi.org/10.1016/j.antiviral.2022.105489
Kouba, T., Drncova, P., & Cusack, S. (2019). Structural snapshots of actively transcribing influenza polymerase. Nature Structural & Molecular Biology, 26(6), 460-470. https://doi.org/10.1038/s41594-019-0232-z
Lee, M. F., Wu, Y. S., & Poh, C. L. (2023). Molecular mechanisms of antiviral agents against dengue virus. Viruses, 15(3), 705. https://doi.org/10.3390/v15030705
Leeson, P. D., Bento, A. P., Gaulton, A., Hersey, A., Manners, E. J., Radoux, C. J., & Leach, A. R. (2021). Target-based evaluation of “drug-like” properties and ligand efficiencies. Journal of medicinal chemistry, 64(11), 7210-7230. https://doi.org/10.1021/acs.jmedchem.1c00416
Li, G., Du, T., Wang, J., Jie, K., Ren, Z., Zhang, X., ... & Ru, H. (2025). Structural insights into the RNA-dependent RNA polymerase complexes from highly pathogenic Marburg and Ebola viruses. Nature Communications, 16(1), 3080. https://doi.org/10.1038/s41467-025-58308-1
Lian, M., Hueffer, K., & Weltzin, M. M. (2022). Interactions between the rabies virus and nicotinic acetylcholine receptors: A potential role in rabies virus induced behavior modifications. Heliyon, 8(9), e10434. https://doi.org/10.1016/j.heliyon.2022.e10434
Ling, M. Y. J., Halim, A. F. N. A., Ahmad, D., Ramly, N., Hassan, M. R., Rahim, S. S. S. A., ... & Hidrus, A. (2023). Rabies in Southeast Asia: a systematic review of its incidence, risk factors and mortality. BMJ Open, 13(5), e066587. https://doi.org/10.1136/bmjopen-2022-066587
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 46(1-3), 3–26. https://doi.org/10.1016/s0169-409x(00)00129-0
Louten, J. (2016). Virus replication. In Essential Human Virology (pp. 49–70). Elsevier. https://doi.org/10.1016/b978-0-12-800947-5.00004-1
Obi, J., Gutiérrez-Barbosa, H., Chua, J., & Deredge, D. (2021). Current trends and limitations in dengue antiviral research. Tropical Medicine and Infectious Disease, 6(4), 180. https://doi.org/10.3390/tropicalmed6040180
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of Computational Chemistry, 25(13), 1605-1612. https://doi.org/10.1002/jcc.20084
Qaisrani, M. N., Belousov, R., Rehman, J. U., Goliaei, E. M., Girotto, I., Franklin-Mergarejo, R., ... & Roldan, E. (2021). Phospholipids dock SARS-CoV-2 spike protein via hydrophobic interactions: A minimal in-silico study of lecithin nasal spray therapy. The European Physical Journal E, 44(11), 132. https://doi.org/10.1140/epje/s10189-021-00137-3
Quiambao, B., Varghese, L., Demarteau, N., Sengson, R. F., Javier, J., Mukherjee, P., ... & Preiss, S. (2020). Health economic assessment of a rabies pre-exposure prophylaxis program compared with post-exposure prophylaxis alone in high-risk age groups in the Philippines. International Journal of Infectious Diseases, 97, 38-46. https://doi.org/10.1016/j.ijid.2020.05.062
Rampersad, S., & Tennant, P. (2018). Replication and Expression Strategies of Viruses. Viruses, 55–82. https://doi.org/10.1016/b978-0-12-811257-1.00003-6
Rieder, M., Brzózka, K., Pfaller, C. K., Cox, J. H., Stitz, L., & Conzelmann, K. K. (2011). Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity. Journal of virology, 85(2), 842-852. https://doi.org/10.1128/jvi.01427-10
Roy, D., Hinge, V. K., & Kovalenko, A. (2019). To pass or not to pass: predicting the blood–brain barrier permeability with the 3D-RISM-KH molecular solvation theory. ACS Omega, 4(16), 16774-16780. https://doi.org/10.1021/acsomega.9b01512
Salvatore, M. M., Andolfi, A., & Nicoletti, R. (2021). The genus Cladosporium: A rich source of diverse and bioactive natural compounds. Molecules, 26(13), 3959. https://doi.org/10.3390/molecules26133959
Sethi, A., Rawlinson, S. M., Dubey, A., Ang, C. S., Choi, Y. H., Yan, F., ... & Gooley, P. R. (2023). Structural insights into the multifunctionality of rabies virus P3 protein. Proceedings of the National Academy of Sciences, 120(14), e2217066120. https://doi.org/10.1073/pnas.2217066120
Song, X. (2024). Antibacterial, antifungal, and antiviral bioactive compounds from natural products. Molecules, 29(4), 825. https://doi.org/10.3390/molecules29040825
Wang, Z. Z., Shi, X. X., Huang, G. Y., Hao, G. F., & Yang, G. F. (2023). Fragment-based drug discovery supports drugging ‘undruggable’protein–protein interactions. Trends in Biochemical Sciences, 48(6), 539-552. https://doi.org/10.1016/j.tibs.2023.01.008
World Health Organization (2024). Rabies (Fact sheet). https://www.who.int/news-room/fact-sheets/detail/rabies
Yuan, Y., Fang, A., Wang, H., Wang, C., Sui, B., Zhao, J., ... & Zhao, L. (2024). Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism. Mbio, 15(3), e02880-23. https://doi.org/10.1128/mbio.02880-23
Zhan, J., Chakraborty, S., Sethi, A., Mok, Y. F., Yan, F., Moseley, G. W., & Gooley, P. R. (2025). Analysis of mechanisms of the rabies virus P protein-nucleocapsid interaction using engineered N-protein peptides and potential applications in antivirals design. Antiviral Research, 234, 106075. https://doi.org/10.1016/j.antiviral.2024.106075
Zhang, S., Krumberger, M., Morris, M. A., Parrocha, C. M. T., Kreutzer, A. G., & Nowick, J. S. (2021). Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists. European Journal of Medicinal Chemistry, 218, 113390. https://doi.org/10.1016/j.ejmech.2021.113390
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Meroy, C., Lim, R., Liwag, K., Maranca, J., Maximo, D., Morales, K., Nalidong, J. and Lirio, M. (2025) “Targeted Molecular Screening of Fungal Metabolites for Blocking Rabies lyssavirus Infection Mechanisms”, International Journal of Advancement in Life Sciences Research, 8(4), pp. 38-54. doi: https://doi.org/10.31632/ijalsr.2025.v08i04.004.
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