Abstract
Dengue, West Nile and Zika, closely related viruses of the Flaviviridae family, are an increasing global threat, due to the expansion of their mosquito vectors. They present a very similar viral particle with an outer lipid bilayer containing two viral proteins and, within it, the nucleocapsid core. This core is composed by the viral RNA complexed with multiple copies of the capsid protein, a crucial structural protein that mediates not only viral assembly, but also encapsidation, by interacting with host lipid systems. The capsid is a homodimeric protein that contains a disordered N-terminal region, an intermediate flexible fold section and a very stable conserved fold region. Since a better understanding of its structure can give light into its biological activity, here, first, we compared and analyzed relevant mosquito-borne Flavivirus capsid protein sequences and their predicted structures. Then, we studied the alternative conformations enabled by the N-terminal region. Finally, using dengue virus capsid protein as main model, we correlated the protein size, thermal stability and function with its structure/dynamics features. The findings suggest that the capsid protein interaction with host lipid systems leads to minor allosteric changes that may modulate the specific binding of the protein to the viral RNA. Such mechanism can be targeted in future drug development strategies, namely by using improved versions of pep14-23, a dengue virus capsid protein peptide inhibitor, previously developed by us. Such knowledge can yield promising advances against Zika, dengue and closely related Flavivirus.
Highlights
Viral hemorrhagic fever is a global problem, with most cases due to dengue virus (DENV), which originates over 390 million infections per year worldwide, being a major socio-economic burden, mainly for tropical and subtropical developing countries [1]
A phylogenetic analysis of the Flavivirus C protein and the polyprotein amino acid residue sequences reveals if the C protein is an indicator of phylogenetic similarity (Figure 1)
C proteins of Spondweni group viruses, i.e., ZIKV, Spondweni virus (SPOV) and Kedougou virus (KEDV), cluster together, being the most similar to DENV (Figure 1a). Another cluster corresponds to mosquito-borne encephalitis-causing Flavivirus: Saint Louis encephalitis (SLEV), WNV, WNV serotype Kunjin (WNV-K), Alfuy (ALFV), Murray Valley encephalitis (MVEV), Usutu (USUV) and Japanese encephalitis (JEV) viruses
Summary
Viral hemorrhagic fever is a global problem, with most cases due to dengue virus (DENV), which originates over 390 million infections per year worldwide, being a major socio-economic burden, mainly for tropical and subtropical developing countries [1]. A working vaccine was registered in Mexico in December 2015, approved for official use in some endemic regions of Latin America and Asia and, as of October 2018, in Europe [2,3,4]. This vaccine is not 100% effective against all DENV serotypes. Research into new prophylactics is still ongoing, with a new vaccine proposed recently being in phase 3 clinical trials [5] In spite of these recent developments, fully effective prophylactics approaches are lacking and there are no effective therapies. This is in part, due to a poor understanding of key steps of the viral life cycle
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