Structural and functional studies of the NS5 RNA-dependent RNA polymerase enzyme from yellow fever virus

• Grant number: 17/16772-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2018
• End date: December 31, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Glaucius Oliva
• Grantee: Victor Gawriljuk Ferraro Oliveira
• Host 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 was a disease of great risk to world health during the XVIII to XX centuries. In the last two years, there has been a resurgence of the yellow fever in the regions of sub-Saharan Africa and the state of Minas Gerais in Brazil. The main consequence of the current outbreaks is the possibility of reurbanization of the disease in Brazil, which can cause yellow fever to be a threat to public health in the country. Nowadays, the only prophylactic method of the disease is the vaccine of attenuated virus 17D. Despite the effectiveness of the vaccine in preventing the disease, there is no drug available for yellow fever so far. Among the available methodologies for the selection of new drugs is the structure-based drug design (SBDD). Based on the three-dimensional structure of validated target proteins, this method uses several computational techniques, always integrated with experimental methods of synthesis and evaluation of the planned compounds, and has been increasingly used for the development of new drugs. The yellow fever virus is a member of the flavivirus family, with genome consisting in a single positive RNA strand that decodes to three structural proteins and seven nonstructural. The yellow fever virus nonstructural protein NS5 has two domains that play central functions to replication of the viral RNA in the infected cell: A RNA-dependent-RNA-polimerase (RdRp) like domain and a metyltransferase domain. The specific blockade of any those functions is lethal to the virus replication. The RpPd domain of the yellow fever virus NS5 does not have a known crystallographic structure. In this project, a crystallographic determination of the RdRp domain structure of the NS5 protein from the circulating yellow fever virus strain is proposed. (AU)