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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2019.tde-04102018-145446
Document
Author
Full name
Leandro Oliveira Bortot
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2018
Supervisor
Committee
Caliri, Antonio (President)
Ito, Amando Siuiti
Araujo, Alexandre Suman de
Carvalho, Ivone
Dias, Luis Gustavo
Title in Portuguese
Mecanismos moleculares de reconhecimento das glicosilações do envelope do vírus da Dengue pelas lectinas tipo-C e seus potenciais inibidores
Keywords in Portuguese
Dengue
Dinâmica molecular
Energia livre
Abstract in Portuguese
Dengue é uma doença tropical negligenciada que atualmente ameaça mais da metade da população mundial e representa custo anual de bilhões de dólares para as áreas afetadas. Avanços recentes na elucidação estrutural de proteínas humanas e vitais contribuíram para o entendimento do ciclo de replicação vital e das interações vírus-hospedeiro a nível molecular. Em particular, a camada mais externa do vírus é composta por 180 monômeros da glicoproteína do envelope. Cada um desses monômeros apresenta duas glicosilações que são reconhecidas por lectinas cuja atividade depende de Ca2+. A interação entre o vírus e essas lectinas favorece a infecção ou o aparecimento de sintomas mais severos. Neste trabalho aplicamos simulações de dinâmica molecular e métodos de estimativa de afinidade para avançar nosso conhecimento sobre os mecanismos moleculares do reconhecimento de glicosilações high-mannose pelas lectinas DC-SIGN e MR, ambas já experimentalmente validadas como alvos biológicos para desenvolvimento de novos antivirais. Adicionalmente, através de virtual screening usando um conjunto de programas de implementação própria e uma biblioteca de moléculas já aprovadas para uso como fármacos, encontramos uma molécula (lohexol) que apresenta alto potencial de interação com ambos os receptores. Embora testes experimentais ainda sejam necessários para validar esse achado, nossos resultados sugerem que essa molécula, e eventualmente moléculas similares, podem agir como inibidor da infecção do vírus da Dengue por um mecanismo duplo.
Title in English
Molecular mechanisms underlying the recognition of the Dengue virus envelope glycosylations by C-Type Lectins and its potential inhibitors
Keywords in English
Dengue
Free energy
Molecular dynamics
Abstract in English
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.
 
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Release Date
2020-10-10
Publishing Date
2019-08-09
 
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