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Antiviral candidates discovery based on the structure of the yellow fever NS5 RNA-dependent RNA polymerase enzyme

Grant number: 18/25773-6
Support type:Scholarships in Brazil - Master
Effective date (Start): May 01, 2019
Effective date (End): May 10, 2021
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Glaucius Oliva
Grantee:Victor Gawriljuk Ferraro Oliveira
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
Associated scholarship(s):19/25407-2 - Development of machine learning models for the discovery of new antiviral compounds against yellow fever virus, BE.EP.MS

Abstract

In the last two years Brazil returned to present yellow fever outbreaks close to large urban centers. The current outbreaks led the Health Ministry on a state of alert, due to the great danger of a disease re urbanization that does not occurs for over 70 years in the country. A mass vaccine campaign was conducted in order to vaccinate the population and control the viral presence in those regions, since the only prophylactic method available is the 17D attenuated virus vaccine. The lack of a treatment for yellow fever, as well as for similar infections, e.g. zika and dengue, highlights the danger of flavivirus for public health. One of the methods used for drug discovery is the structure based drug design. In which, based on the three dimensional structure of a validated target-protein the method utilizes different computational techniques always allied with experimental methods of synthesis and evaluation to the optimization of a ligand. The yellow fever virus is a member of the Flaviviridae family, its genome consists of a single positive sense RNA strand that codifies for three structural and seven non structural proteins. The yellow fever virus non structural protein NS5 contain two domains that play central roles for viral RNA replication: one RNA-dependent RNA polymerase (RdRp) and a methyltransferase domain. The specific blockade of any those domains is lethal for viral replication. The yellow fever virus RdRp does not have a known crystallographic model. In this project we propose the structural elucidation of the yellow fever RdRp followed by drug discovery using structure based drug design. (AU)