Structural and functional studies of the NS2B-NS3 protease complex from yellow fever

Abstract

The first reports of yellow fever dates from the XVII century in Mexico. During the period of the XVII and XIX centuries, the epidemics reach the whole world. With the development of a vaccine, the disease stays restrict in endemic areas and there were only few cases reported. In Brazil, there was no case reported of urban yellow fever since 1942, although the virus never stopped circulating in wild areas. However, the increase of the non-immunized population, the expansion of urban areas in contact with wild repositories of the virus, and global warming created a favorable environment to the resurgence of the disease on the global scenario, putting back the yellow fever has an international public health concern. Despite the historical of the disease, there still no drugs available for the yellow fever treating the infection, and prophylactic methods are the only alternative. Today, one of the most used methods to discover for new drugs is the Structural-Based Drug Design method. Using the tridimensional structure of a target protein, we can use computational methods to identify possible compounds that interact with a specific site, making easier the search for a potential drug candidate. The yellow fever virus is an Arbovirus of the genus Flavivirus, and has its genetic material composed by a single stranded positive sense RNA that encodes a single polyprotein containing three structural proteins and seven non-structural. The polyprotein is cleaved by one of the non-structural proteins, a NS3 protease, that acts associated with another non-structural protein as cofactor, the NS2B. The activity of this complex is essential to the virus replication, being an important target for drug development for other Flavivirus, like dengue and Zika. Until the moment there is no crystallographic structure of the NS3-NS2B protease. The proposal of this project is to elucidate the X-ray structure of the NS3-NS2B protease of yellow fever that belongs to the circulating lineage in Brazil during the outbreak in the southeast states in 2017, as well as the proposal of possible inhibitors candidates for this protein. (AU)