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Antiviral Agents

Design and Validation of Novel Chikungunya Virus Protease Inhibitors

Pratyush Kumar Das, Laura Puusepp, Finny S. Varghese, Age Utt, Tero Ahola, Dzmitry G. Kananovich, Margus Lopp, Andres Merits, Mati Karelson
Pratyush Kumar Das
aInstitute of Technology, University of Tartu, Tartu, Estonia
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Laura Puusepp
bInstitute of Chemistry, University of Tartu, Tartu, Estonia
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Finny S. Varghese
cDepartment of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland
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Age Utt
aInstitute of Technology, University of Tartu, Tartu, Estonia
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Tero Ahola
cDepartment of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland
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Dzmitry G. Kananovich
dDepartment of Chemistry, Tallinn University of Technology, Tallinn, Estonia
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Margus Lopp
dDepartment of Chemistry, Tallinn University of Technology, Tallinn, Estonia
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Andres Merits
aInstitute of Technology, University of Tartu, Tartu, Estonia
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Mati Karelson
bInstitute of Chemistry, University of Tartu, Tartu, Estonia
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DOI: 10.1128/AAC.01421-16
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ABSTRACT

Chikungunya virus (CHIKV; genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast, there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2. The available three-dimensional (3D) structure of nsP2 protease has made it a target for in silico drug design; however, there is thus far little evidence that the designed compounds indeed inhibit the protease activity of nsP2 and/or suppress CHIKV replication. In this study, a set of 12 compounds, predicted to interact with the active center of nsP2 protease, was designed using target-based modeling. The majority of these compounds were shown to inhibit the ability of nsP2 to process recombinant protein and synthetic peptide substrates. Furthermore, all compounds found to be active in these cell-free assays also suppressed CHIKV replication in cell culture, the 50% effective concentration (EC50) of the most potent inhibitor being ∼1.5 μM. Analysis of stereoisomers of one compound revealed that inhibition of both the nsP2 protease activity and CHIKV replication depended on the conformation of the inhibitor. Combining the data obtained from different assays also indicates that some of the analyzed compounds may suppress CHIKV replication using more than one mechanism.

FOOTNOTES

    • Received 1 July 2016.
    • Returned for modification 29 July 2016.
    • Accepted 20 September 2016.
    • Accepted manuscript posted online 10 October 2016.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.01421-16.

  • Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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Design and Validation of Novel Chikungunya Virus Protease Inhibitors
Pratyush Kumar Das, Laura Puusepp, Finny S. Varghese, Age Utt, Tero Ahola, Dzmitry G. Kananovich, Margus Lopp, Andres Merits, Mati Karelson
Antimicrobial Agents and Chemotherapy Nov 2016, 60 (12) 7382-7395; DOI: 10.1128/AAC.01421-16

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Design and Validation of Novel Chikungunya Virus Protease Inhibitors
Pratyush Kumar Das, Laura Puusepp, Finny S. Varghese, Age Utt, Tero Ahola, Dzmitry G. Kananovich, Margus Lopp, Andres Merits, Mati Karelson
Antimicrobial Agents and Chemotherapy Nov 2016, 60 (12) 7382-7395; DOI: 10.1128/AAC.01421-16
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