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Characterization of small molecule inhibitors of Zika Virus infection

Title: Characterization of small molecule inhibitors of Zika Virus infection.
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Name(s): Allen, Chase Terrance, author
Type of Resource: text
Genre: Text
Bachelor Thesis
Date Issued: 2017-04-27
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Zika virus (ZIKV) is a mosquito-transmitted positive RNA sense virus that has spread rapidly in the past year, prompting the World Health Organization (WHO), on 1 February 2016, to announce that the association of Zika infection with clusters of microcephaly and other neurological disorders constituted a Public Health Emergency of International Concern1. The state of emergency eventually ended in November of 2016; however, given the global health concern posed by this virus, a large-scale effort to identify drugs for treating ZIKV and combatting its continued spread is of utmost importance. There are currently no drugs or vaccines for the treatment or prevention of ZIKV infection, although at least one vaccine study is scheduled for stage II/IIb clinical trials. This vaccine is currently being developed by the National Institute of Allergy and Infectious Diseases (NIAID), a branch of the National Institutes of Health (NIH). Although this vaccine study is underway, it is still highly advantageous to have small molecule inhibitors because whether or not this vaccination will produce susceptibilities to secondary flavivirus infections is still unknown42. The urgency that this situation provides led us and others to look to test preexisting drugs for efficacy against ZIKV infection. In attempt to close this gap in treatment and prevention we, in collaboration with Dr. Wei Zheng and others at the National Center for Advanced Translational Sciences (NCATS), previously reported a screen of 6,000 compounds for anti-ZIKV activity. In this study, we identified several compounds with sub-micromolar anti-ZIKV activity in a cell-culture based model, including the FDA approved anthelmintic drug Niclosamide. Niclosamide proved to be capable of inhibiting ZIKV replication at ~0.2μM concentrations, in vitro, when added either before or after ZIKV exposure2. In order to pursue additional potential drugs, our collaborative efforts have, in total, screened over 80,000 compounds for anti-ZIKV activity. Of these, we have selected several compounds for characterization, based on multiple factors: initial antiviral activity in a ZIKV viral protein (non-structural protein 1) detection assay, cytotoxicity profiles, and US Food and Drug Administration (FDA) approval status or previous in vivo safety profiles via human clinical trials. Attempts to further characterize the anthelmintic drug Niclosamide as well as efforts to identify several more compounds for antiviral activity were explored in a cell culture based ZIKV model for efficacy against ZIKV infection and drug anti-ZIKV mechanism of action. My results demonstrate the efficacy of these screening techniques, identify potential compounds for anti-ZIKV drug development, and provide preliminary insights on the selected drug mechanisms of action.
Identifier: FSU_libsubv1_scholarship_submission_1493319376 (IID)
Keywords: Small molecules, Zika Virus, ZIKV, Mitoxantrone, Niclosamide
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1493319376
Owner Institution: FSU

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Allen, C. T. (2017). Characterization of small molecule inhibitors of Zika Virus infection. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1493319376