Screening of compounds using biochemical and biophysical techniques applied to the helicase domain of the non-structural protein 3 of the Zika Virus (ZIKV_NS3Hel) and the open access plates of the Medicines for Malaria Venture (MMV)

• Grant number: 24/18206-9
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 10, 2025
• End date: February 27, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Glaucius Oliva
• Grantee: Ana Júlia Sousa Marinho
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Flaviviruses causing Dengue and Zika have been a major public health challenge in Brazil due to the climatic conditions favorable to the spread of their vector, Aedes aegypti. The numerous Zika virus (ZIKV) infections caused concern in the medical community due to their association with serious neurological complications: Guillain-Barré Syndrome in adults and Congenital ZIKV Syndrome in newborns, which occurred during the epidemic and still persist to this day. Although the situation with Zika Fever in Brazil has attenuated, cases still occur in the country. Additionally, the discovery of a new strain of circulating ZIKV in the country has raised an alert for the possibility of a new epidemic. Despite the still urgent medical needs, there are currently no vaccines or therapeutic agents available for ZIKV, motivating the search for potential drug candidates. Two processes are critical for the virus's life cycle in the human host: infection and/or replication. The replication process essentially depends on non-structural proteins encoded by the viral genome. NS3 has two protein domains: serine protease (NS3Pro) and NTP-dependent RNA helicase (NS3Hel), responsible respectively for the cleavage of polyproteins after translation and the unwinding of double-stranded RNA before RNA polymerization and capping. Thus, the central goal of this project is to evaluate and optimize the binding capacity and inhibition of the RNA-unwinding activities of the ZIKV helicase by the Open Access compounds made available by the Medicines for Malaria Venture (MMV). Compounds efficient in inhibiting these activities will be subjected to HQSAR (Quantitative Structure-Activity Relationships) studies and cycles of design and synthesis of analogs, seeking to maximize their affinity for the target enzyme.