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Title: Bortezomib inhibits chikungunya virus replication by interfering with viral protein synthesis.
Authors: Kaur, Parveen 
Lello, Laura Sandra
Utt, Age
Dutta, Sujit Krishna
Merits, Andres
Chu, Justin Jang Hann 
Issue Date: 29-May-2020
Publisher: Public Library of Science (PLoS)
Citation: Kaur, Parveen, Lello, Laura Sandra, Utt, Age, Dutta, Sujit Krishna, Merits, Andres, Chu, Justin Jang Hann (2020-05-29). Bortezomib inhibits chikungunya virus replication by interfering with viral protein synthesis.. PLoS Neglected Tropical Diseases 14 (5) : e0008336-. ScholarBank@NUS Repository.
Abstract: Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness accompanied by myalgia and arthralgia. Despite having re-emerged as a significant public health threat, there are no approved therapeutics or prophylactics for CHIKV infection. In this study, we explored the anti-CHIKV effects of proteasome inhibitors and their potential mechanism of antiviral action. A panel of proteasome inhibitors with different functional groups reduced CHIKV infectious titers in a dose-dependent manner. Bortezomib, which has been FDA-approved for multiple myeloma and mantle cell lymphoma, was further investigated in downstream studies. The inhibitory activities of bortezomib were confirmed using different cellular models and CHIKV strains. Time-of-addition and time-of-removal studies suggested that bortezomib inhibited CHIKV at an early, post-entry stage of replication. In western blot analysis, bortezomib treatment resulted in a prominent decrease in structural protein levels as early as 6 hpi. Contrastingly, nsP4 levels showed strong elevations across all time-points. NsP2 and nsP3 levels showed a fluctuating trend, with some elevations between 12 to 20 hpi. Finally, qRT-PCR data revealed increased levels of both positive- and negative-sense CHIKV RNA at late stages of infection. It is likely that the reductions in structural protein levels is a major factor in the observed reductions in virus titer, with the alterations in non-structural protein ratios potentially being a contributing factor. Proteasome inhibitors like bortezomib likely disrupt CHIKV replication through a variety of complex mechanisms and may display a potential for use as therapeutics against CHIKV infection. They also represent valuable tools for studies of CHIKV molecular biology and virus-host interactions.
Source Title: PLoS Neglected Tropical Diseases
ISSN: 19352727
DOI: 10.1371/journal.pntd.0008336
Appears in Collections:Staff Publications

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