Respiratory Syncytial Viral Infection is one of the most common viral infections in the respiratory airways and is more common in infants, younger children and some adults. Although ribavirin has been used in the management of RSV infection, many effective drugs are still under development. Also, structured based drug design using computational tools has shifted the paradigm of drug design and discovery. The fusion core of the Respiratory Syncytial Viral (RSV) structure is crucial for its fusion, entry and replication in the host cell. Herein, we investigated the interruption of the formation and/or the stability of the fusion core. 15 ligands were screened and 4 (Glimepiride, Glipizide, Canagloflozin, Glibenclamide) of them are potential drug candidate for experimental validation, preclinical trials, clinical trials and route of administration optimization. To the best of our knowledge, this is the first time of reporting lead molecules against RSV from oral hypoglycemic agents. It also suggests the ligands for consideration as prophylactics in infants and adults via the inhalation route.
References
[1]
Hall, C.B., Weinberg, G.A., Iwane, M.K., Blumkin, A.K., Edwards, K.M., Staat, M.A., Auinger, P., Griffin, M.R., Poehling, K.A., Erdman, D., et al. (2009) The Burden of Respiratory Syncytial Virus Infection in Young Children. The New England Journal of Medicine, 360, 588-598. https://doi.org/10.1056/NEJMoa0804877
[2]
Nair, H., Nokes, D.J., Gessner, B.D., Dherani, M., Madhi, S.A., Singleton, R.J., O'Brien, K.L., Roca, A., Wright, P.F., Bruce, N., et al. (2010) Global Burden of Acute Lower Respiratory Infections Due to Respiratory Syncytial Virus in Young Children: A Systematic Review and Meta-Analysis. The Lancet, 375, 1545-1555.
https://doi.org/10.1016/S0140-6736(10)60206-1
[3]
Sun, Z.W., Pan, Y.B., Jian, S.B. and Lu, L. (2013) Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein: A Review. Viruses, 5, 211-225.
https://doi.org/10.3390/v5010211
[4]
Yoon, J.-J., Toots, M., Lee, S., Lee, M.-E., Ludeke, B., Luczo, J.M., et al. (2018) Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses. ASM Journals Antimicrobial Agents and Chemotherapy, 62, e00766-18. https://doi.org/10.1128/AAC.00766-18
[5]
Collins, P.L. and Melero, J.A. (2011) Progress in Understanding and Controlling Respiratory Syncytial Virus: Still Crazy after All These Years. Virus Research, 162, 80-99. https://doi.org/10.1016/j.virusres.2011.09.020
[6]
Teng, M.N., Whitehead, S.S. and Collins, P.L. (2001) Contribution of the Respiratory Syncytial Virus G Glycoprotein and Its Secreted and Membrane-Bound Forms to Virus Replication in Vitro and in Vivo. Virology, 289, 283-296.
https://doi.org/10.1006/viro.2001.1138
[7]
Tayyari, F., Marchant, D., Moraes, T.J., Duan, W.M., Mastrangelo, P. and Hegele, R.G. (2011) Identification of Nucleolin as a Cellular Receptor for Human Respiratory Syncytial Virus. Nature Medicine, 17, 1132-1135.
https://doi.org/10.1038/nm.2444
[8]
Baker, K.A., Dutch, R.E., Lamb, R.A. and Jardetzky, T.S. (1999) Structural Basis for Paramyxovirus-Mediated Membrane Fusion. Molecular Cell, 3, 309-319.
https://doi.org/10.1016/S1097-2765(00)80458-X
[9]
Campbell, G.R., To, R.K., Hanna, J. and Spector, S.A. (2021) SARS-CoV-2, SARS-CoV-1, and HIV-1 Derived ssRNA Sequences Activate the NLRP3 Inflammasome in Human Macrophages through a Non-Classical Pathway. iScience, 24, Article ID: 102295. https://doi.org/10.1016/j.isci.2021.102295
[10]
Das, S., Sarmah, S., Lyndem, S. and Singha Roy, A. (2021) An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study. Journal of Biomolecular Structure and Dynamics, 39, 3347-3357.
https://doi.org/10.1080/07391102.2020.1763201
[11]
Naithani, R., et al. (2008) Antiviral Activity of Phytochemicals: A Comprehensive Review. Mini-Reviews in Medicinal Chemistry, 8, 1106-1133.
https://doi.org/10.2174/138955708785909943
[12]
Lopes, B.R.P., da Costa, M.F., Ribeiro, A.G., et al. (2020) Quercetin Pentaacetate Inhibits in Vitro Human Respiratory Syncytial Virus Adhesion. Virus Research, 27, Article ID: 197805. https://doi.org/10.1016/j.virusres.2019.197805
[13]
Choudhuri, S., Symons, J.A. and Deval, J. (2018) Innovation and Trends in the Development and Approval of Antiviral Medicines: 1987-2017 and Beyond. Antiviral Research, 155, 76-88. https://doi.org/10.1016/j.antiviral.2018.05.005
[14]
Morris, G., Huey, R., Lindstrom, W., et al. (2009) AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry, 30, 2785-2791. https://doi.org/10.1002/jcc.21256
[15]
Khaerunnisa, S., Kurniawan, H., Awaluddin, R., Suhartati, S. and Soetjipto, S. (2020) Potential Inhibitor of COVID-19 Main Protease (Mpro) from Several Medicinal Plant Compounds by Molecular Docking Study.
https://doi.org/10.20944/preprints202003.0226.v1
[16]
Dallakyan, S. and Olson, A.J. (2015) Small-Molecule Library Screening by Docking with PyRx. Chemical Biology Methods and Protocols, 1263, 243-250.
https://doi.org/10.1007/978-1-4939-2269-7_19
[17]
Pagadala, N.S., Syed, K. and Jack, T. (2017) Software for Molecular Docking: A Review. Biophysical Reviews, 9, 91-102. https://doi.org/10.1007/s12551-016-0247-1
[18]
Diana, O.M. and Zoete, V. (2017) SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug Likeness and Medicinal Chemistry Friendliness of Small Molecules. Scientific Reports, 7, Article No. 42717.
[19]
Roymans, D., De Bondt, H.L., Arnoult, E., Geluykens, P., Gevers, T., Van Ginderen, M., Verheyen, N., et al. (2009) Binding of a Potent Small-Molecule Inhibitor of Six-Helix Bundle Formation Require Interactions with both Heptad-Repeats of the RSV Fusionprotein. PNAS, 107, 308-313. https://doi.org/10.1073/pnas.0910108106
