Design and Validation of Novel Chikungunya Virus Protease Inhibitors

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Das , P K , Puusepp , L , Varghese , F S , Utt , A , Ahola , T , Kananovich , D G , Lopp , M , Merits , A & Karelson , M 2016 , ' Design and Validation of Novel Chikungunya Virus Protease Inhibitors ' Antimicrobial Agents and Chemotherapy , vol. 60 , no. 12 , pp. 7382-7395 . DOI: 10.1128/AAC.01421-16

Title: Design and Validation of Novel Chikungunya Virus Protease Inhibitors
Author: Das, Pratyush Kumar; Puusepp, Laura; Varghese, Finny S.; Utt, Age; Ahola, Tero; Kananovich, Dzmitry G.; Lopp, Margus; Merits, Andres; Karelson, Mati
Contributor: University of Helsinki, Genome-Scale Biology (GSB) Research Program
University of Helsinki, Department of Food and Nutrition
University of Helsinki, Department of Food and Nutrition
Date: 2016-12
Language: eng
Number of pages: 14
Belongs to series: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804
URI: http://hdl.handle.net/10138/172498
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 similar to 1.5 mu M. 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.
Subject: EQUINE ENCEPHALITIS-VIRUS
RESONANCE ENERGY-TRANSFER
VIRAL MACRO DOMAINS
NONSTRUCTURAL PROTEIN-2
NSP2 PROTEASE
POLYPROTEIN CLEAVAGE
ANTIVIRAL ACTIVITY
SINDBIS VIRUS
RNA-SYNTHESIS
REPLICATION
1183 Plant biology, microbiology, virology
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