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Preliminary processes of viral infection: stereochemical study of the E protein of Dengue

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Ricardo Oliveira dos Santos Soares
Total Authors: 1
Document type: Doctoral Thesis
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto
Defense date:
Examining board members:
Antonio Caliri; Pietro Ciancaglini; Antônio José da Costa Filho; Pedro Geraldo Pascutti
Advisor: Antonio Caliri

Dengue infection burdens all tropical and subtropical regions of the globe, registers approximately 390 million cases annually, and stands out as an emerging problem of increasing proportions, especially in Brazil, which currently accounts for 60% of cases in the American continent. Thus, actions to create, adapt and meet conditions to promote advances in understanding the process of virus infection at the molecular level can be of great value both to meet the challenges posed by current conjuncture of dengue, and for the possibility to extend the knowledge of the molecular mechanisms to related viruses. Here, focusing on the E protein of the dengue virus envelope, we address the problem of viral infection under stereochemical aspects of the envelope (E) protein when it undergoes the distinct environmental conditions along the pathway from the exothermic vector\'s digestive tract to the homeothermic host\'s cell machinery. To this end, we employ molecular dynamics to assess and quantify the processes of conformational rearrangement of isolated domain III of the E protein of the four serotypes of dengue, as induced by changes on intensive thermodynamic parameters (pH 3, 5 and 7; T = 298K and 310K). Further, the 5-fold quaternary configuration of five domains III is studied, correlating specific loop regions flexibilities with induced fit with eventual ligands. We also check the structural stability and interaction forces between the interface of the complex DIII and the antigen binding fragment of a monoclonal antibody (Fab 1A1D-2), identifying key residues. Additionally events related to the interaction of the E protein (both as a monomer and as a dimer) with the viral membrane are thoroughly studied, paving the way for a possible study focused on the formation of trimers of E protein, leading to membrane fusion and subsequent inoculation of viral RNA in the cytoplasm. Finally, alternatives are proposed for understanding the mechanism of action of the phospholipase from the venom of Crotalus durissus terrificus - the South American rattlesnake, which has proven effective in vitro inhibition of Dengue virus infection. (AU)

FAPESP's process: 09/08700-6 - Initial viral infection stage: stereo-chemical study of (glico)protein E envelope of the dengue virus
Grantee:Ricardo Oliveira dos Santos Soares
Support type: Scholarships in Brazil - Doctorate