A cell-based high throughput screening strategy for Chikungunya drug discovery

• Grant number: 16/03780-5
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): September 01, 2016
• Effective date (End): February 28, 2019
• Field of knowledge: Biological Sciences - Microbiology
• Principal Investigator: Lucio Holanda Gondim de Freitas Junior
• Grantee: Rafaela Milan Bonotto
• Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Chikungunya virus (CHIKV), an arbovirus belonging to the family Togavirideae, is the causative agent of Chikungunya Fever. Chikungunya is re-emerging as a significant public health problem and was responsible for a massive outbreak in Asia in 2006, and since then regular epidemics have occurred worldwide. A main concern with CHKV is that it is transmitted by the ubiquitous urban mosquito Aedes sp., better known as the Dengue virus vector, and therefore there is a risk of Chikungunya spreading in areas where dengue is endemic. Although CHIKV causes a disease that in its acute phase resembles dengue, with high fever, rash, severe chronic join pain and persistent arthralgia, Chikungunya can develop into a chronic infection and last up to several months. As for dengue, there is no specific antiviral treatment for Chikungunya; to address drug discovery needs and R&D gaps in the pipeline, a cell-based, CHIKV High Throughput Screening (HTS) assay was recently developed by our group. This PhD thesis project focuses on drug discovery for Chikungunya and the main objectives of this project are: 1) to use the CHIKV HTS assay for screening a compound collection of thousands of drug-like compounds, resulting in hit compounds that will be synthetically optimized in collaboration with a Medicinal Chemistry team for improvement of its drug properties; and 2) study of the most active antiviral compounds mechanism of action on CHIKV infection, thus using the compounds as chemical probes to deepen our understanding of the infection process and ultimately of the pathogenesis of CHIKV. This project is expected to result in the first ever-developed lead compounds for Chikungunya drug discovery. (AU)