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Characterization of the mode of action of a potent dengue virus capsid inhibitor

Scaturro, P., Trist, I. M. L., Paul, D., Kumar, A., Acosta, E. G., Byrd, C. M., Jordan, R., Brancale, Andrea and Bartenschlager, R. 2014. Characterization of the mode of action of a potent dengue virus capsid inhibitor. Journal of Virology 88 (19) , pp. 11540-11555. 10.1128/JVI.01745-14

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Abstract

Dengue viruses (DV) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. In spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of DV infection. We have previously reported the identification of ST-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against DV in vitro and in vivo (C. M. Byrd et al., Antimicrob. Agents Chemother. 57:15–25, 2013, doi:10 .1128/AAC.01429-12). In the present study, we investigated the mode of action of this promising compound by using a combination of biochemical, virological, and imaging-based techniques. We confirmed that ST-148 targets the capsid protein and obtained evidence of bimodal antiviral activity affecting both assembly/release and entry of infectious DV particles. Importantly, by using a robust bioluminescence resonance energy transfer-based assay, we observed an ST-148-dependent increase of capsid self-interaction. These results were corroborated by molecular modeling studies that also revealed a plausible model for compound binding to capsid protein and inhibition by a distinct resistance mutation. These results suggest that ST-148-enhanced capsid protein self-interaction perturbs assembly and disassembly of DV nucleocapsids, probably by inducing structural rigidity. Thus, as previously reported for other enveloped viruses, stabilization of capsid protein structure is an attractive therapeutic concept that also is applicable to flaviviruses.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: Q Science > QR Microbiology > QR355 Virology
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Society for Microbiology
ISSN: 0022-538X
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 18 July 2014
Last Modified: 27 Jun 2019 13:31
URI: http://orca-mwe.cf.ac.uk/id/eprint/69387

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