Journal
ANTIVIRAL RESEARCH
Volume 103, Issue -, Pages 7-16Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2013.12.010
Keywords
CHIKV nsP4; CHIKV nsP3; HSP-90; Geldanamycin; Protein interactions; CHIKV mouse model
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Funding
- Duke-NUS signature research program
- Agency for Science, Technology and Research, Singapore
- Ministry of Health, Singapore
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The global emergence of Chikungunya virus (CHIKV) infection is alarming and currently there is no licensed vaccine or antiviral treatment available to mitigate this disease. CHIKV infection typically results in high viral load with an outcome of high fever, skin rashes, muscle pain, and sequelae of prolonged arthritis, which occurs in >90% of the infected cases. In this study, using biochemical pull-downs, mass-spectrometry, and microscopic imaging techniques, we have identified novel interactions between CHIKV nsP3 or nsP4 proteins with the host stress-pathway chaperone HSP-90 protein. Indeed, silencing of HSP-90 transcripts using siRNA disrupts CHIKV replication in cultured cells. Furthermore, drugs targeting HSP-90, such as commercially available geldanamycin, as well as other specific HSP-90 inhibitor drugs that had been obtained from a purinome mining approach (HS-10 and SNX-2112) showed dramatic reduction in viral titers and reduced inflammation in a CHIKV mouse model of severe infection and musculopathy. The detailed study of the underlying molecular mechanism of these viral and host protein interactions may provide a platform to develop novel therapeutics against CHIKV infection. (C) 2013 Elsevier B.V. All rights reserved.
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