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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/1178
Title: Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection
Authors: Fatma B.
Kumar R.
Singh V.A.
Nehul S.
Sharma R.
Kesari P.
Kuhn R.J.
Tomar S.
Published in: Antiviral Research
Abstract: Chikungunya virus (CHIKV) is an arthritogenic alphavirus and currently, no antiviral drug is available to combat it. Capsid protein (CP) of alphaviruses present at the N-terminus of the structural polyprotein possesses auto-proteolytic activity which is essential for initiating the structural polyprotein processing. We are reporting for the first time antiviral molecules targeting capsid proteolytic activity. Structure-assisted drug-repositioning identified three molecules: P1,P4-Di(adenosine-5?) tetraphosphate (AP4), Eptifibatide acetate (EAC) and Paromomycin sulphate (PSU) as potential capsid protease inhibitors. A FRET-based proteolytic assay confirmed anti-proteolytic activity of these molecules. Additionally, in vitro cell-based antiviral studies showed that EAC, AP4, and PSU drastically stifled CHIKV at the post-entry step with a half-maximal effective concentration (EC50) of 4.01 ?M, 10.66 ?M and 22.91 ?M
respectively. Interestingly, the inhibitors had no adverse effect on viral RNA synthesis and treatment of cells with inhibitors diminished levels of CP in virus-infected cells, which confirmed inhibition of capsid auto-proteolytic activity. In conclusion, the discovery of antiviral molecules targeting capsid protease demystifies the alphavirus capsid protease as a potential target for antiviral drug discovery. © 2020 Elsevier B.V.
Citation: Antiviral Research(2020), 179(): -
URI: https://doi.org/10.1016/j.antiviral.2020.104808
http://repository.iitr.ac.in/handle/123456789/1178
Issue Date: 2020
Publisher: Elsevier B.V.
Keywords: Antiviral
Capsid protein
Chikungunya
Drug repositioning
Protease
ISSN: 1663542
Author Scopus IDs: 57191071112
57209875422
57201632985
57195303343
57209347974
57218355625
7202460038
57203506001
Author Affiliations: Fatma, B., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Kumar, R., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Singh, V.A., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Nehul, S., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Sharma, R., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Kesari, P., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Kuhn, R.J., Department of Biological Sciences, And Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West LafayetteIN, United States
Tomar, S., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Funding Details: This research was supported by the Science and Engineering Research Board, Department of Science & Technology, Government of India (grant- EMR/2016/004938 ). BF and SN thanks Ministry of Human Resource Development, Government of India for financial support. RK acknowledges support from the Science and Engineering Research Board, Department of Science & Technology, Government of India for National Post-Doctoral Fellowship (grant- PDF/2017/00649 ). VAS, ST and RJK acknowledges Science and Engineering Research Board, Department of Science & Technology, Government of India for OVDF fellowship (grant- SB/S9/Z-03/2017-V (2018–19). We also thank Jacqueline Anderson (Graduate student, Department of Biological Sciences, Purdue University) for her constructive criticism on the manuscript.
Corresponding Author: Tomar, S.; Department of Biotechnology, Indian Institute of Technology, RoorkeeIndia; email: shailly.tomar@bt.iit.ac.in
Appears in Collections:Journal Publications [BT]

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