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Discovery and development of antiviral candidates against Yellow Fever virus based on the structure of the NS2B-NS3 protease complex

Grant number: 18/25600-4
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2019
Effective date (End): February 28, 2023
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Glaucius Oliva
Grantee:Gabriela Dias Noske
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Associated research grant:13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

The Yellow Fever Virus (YFV) has its genome composed by a single strand positive RNA and belongs to the genre flavivirus that includes Dengue, Zika and Hepatitis C. Despite of the historical of the disease, still there are no drugs for the treatment of the Yellow Fever. In Brazil, although the vaccination maintained the disease in control, a recent outbreak in the beginning of 2017 putted back the Yellow Fever as a public health concern, due the risks of a new spread on the urban environment. The Yellow Fever genome codifies a unique polyprotein that contains three structural and seven non-structural proteins. The NS3 contains two domains: a protease domain (NS3Pro) and a helicase/NTP-ase domain (NS3Hel). The NS3 protease acts together with the C-terminal portion of another non-structural protein, the NS2B, which helps the correct folding of the NS3 protease, acting as cofactor and allowing to be in its active form. The NS2B-NS3Pro complex cleaves the immature polyprotein, releasing the mature proteins that form the viral replication complex. Considering the importance of this complex in the viral replication cycle, it is a key target to the search and development of potential antiviral candidates. Nowadays, the Structure-Based Drug Design (SBDD) had became one of the most used methods for drug discovery. Allying computational and experimental methods, allows the ligand optimization by complementarity of the ligand and receptor, moreover, reduce the price and time of the ligand search using the molecular docking. Thus, the main objective of this project is to elucidate the crystallographic structure of the NS2B-NS3Pro complex of the circulating lineage of the Yellow Fever virus and its utilization to propose possible antiviral candidates. In this project, will be applied the SBDD, starting with the expression, purification, biochemical and biophysical characterization and crystallization of the NS2B-NS3Pro complex of the circulating lineage of YFV. In the following step, we will do the search for inhibitors using computational methods. The ligands obtained will be optimized based on the affinity for the receptor and pharmacokinetics and pharmacodynamics parameters such as permeability and cytotoxicity. In the end of the project, we intend to obtain at least one potential drug lead that could be further optimized into a pre-clinical molecule. (AU)