Molecular mechanisms underlying the recognition of the Dengue virus envelope glycosylations by C-Type Lectins and its potential inhibitors

Author(s)

Leandro Oliveira Bortot

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2018-05-16

Examining board members

Antonio Caliri; Alexandre Suman de Araujo; Ivone Carvalho; Luis Gustavo Dias

• Advisor: Antonio Caliri

Abstract

Dengue is a tropical neglected disease that currently threatens more than half the world\'s population and represents a yearly cost of billions of dollars to the affected areas. Recent advances in the elucidation of 3D structures of human and viral proteins has contributed to the understanding of the viral replication cycle and virus-host interactions at the molecular level. In particular, the outermost layer of the virus is composed by 180 monomers of the envelope glycoprotein. Each one of these monomers displays two glycosylations that are recognized by lectins which have Ca2+-dependent activity. The interaction between the virus and these lectins favors infection or severe disease onset. In this work we apply molecular dynamics simulations and affinity estimation methods to advance our knowledge about the molecular mechanisms underlying the recognition of the high-mannose glycosylation by the DC-SIGN and MR lectins, both of which are already validated as targets for the development of new antivirals against Dengue. Additionally, by running virtual screening assays using a set of programs implemented by us and a library containing molecules which are already approved to be used as drugs, we found one molecule (lohexol) which presents high potential of interaction with both receptors. Although experimental testing is still necessary to validate this finding, our results suggest that this molecule, and eventually similar ones, can act as an inhibitor of the Dengue virus infection by a dual mechanism. (AU)

• FAPESP's process: 13/00927-7 - Molecular dynamics simulations for the identification of bioactive molecules: inhibitors of the interaction between the dengue virus envelope glycoprotein and cellular C-type lectins
• Grantee: Leandro Oliveira Bortot
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)