Attacking dengue on two fronts: using computer simulations to develop new antiviral compounds and vaccines

• Grant number: 22/00347-0
• Support Opportunities: Scholarships abroad - Research
• Start date: February 01, 2023
• End date: July 31, 2023
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Alexandre Suman de Araujo
• Grantee: Alexandre Suman de Araujo
• Host Investigator: Walter Rocchia
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
• Institution abroad: Istituto Italiano di Tecnologia (IIT), Italy
• Associated research grant(s): 25/02641-0 - Protein Electrostatics Conference, AR.EXT

Abstract

Dengue Fever is one of the most relevant arboviruses affecting humans, primarily spread by female mosquitoes of the Aedes genus, infecting about 390 million individuals annually, and leading to 500,000 hospitalizations. The cause of Dengue fever is an enveloped virus of spherical shape belonging to the Flaviviridae family. The envelope protein (protein E) is a crucial viral protein because it is the sole target of neutralizing antibodies and contains an amino acids sequence called fusion peptide. In its fusogenic conformation, protein E forms projections on the virus surface exposing the fusion peptide which interacts with the endosomal membrane, leading to the injection of the virus's genetic material into the cell. The potent broadly neutralizing antibody 752-2 C8 (C8) is effective against the four Dengue virus serotypes and its recognition determinants are at a serotype-invariant site at the protein E dimer interface, including the exposed main chain of the protein E fusion loop. Exploring the nature of the interactions that govern these systems can significantly contribute to the development of antiviral compounds and vaccines. In this project, we propose using computer simulations to investigate these interactions using equilibrium Molecular Dynamics (MD), Free energy calculations, and Constant pH Molecular Dynamics (CpHMD). (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HERNANDEZ GONZALEZ, JORGE ENRIQUE; DE ARAUJO, ALEXANDRE SUMAN. Alchemical Calculation of Relative Free Energies for Charge-Changing Mutations at Protein-Protein Interfaces Considering Fixed and Variable Protonation States. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 63, n. 21, p. 16-pg., 2023-10-18. (22/00347-0, 20/10214-1, 22/03901-8)

CASTELUCI, G.; DIAS, R. V. R.; MARTINS, I. B. S.; FERNANDES, R. A.; TEDESCO, J. A.; CARUSO, I. P.; DE ARAUJO, A. S.; ITRI, R.; MELO, F. A.. Grb2 Y160F mutant mimics the wild-type monomeric state dynamics and the monomer-dimer equilibrium. International Journal of Biological Macromolecules, v. 279, p. 9-pg., 2024-08-30. (22/00347-0, 16/13884-2, 23/09642-7, 19/24974-0, 23/01632-2, 23/01744-5)

MARTINS, INGRID B. S.; VIEGAS, RAFAEL G.; SANCHES, MURILO N.; DE ARAUJO, ALEXANDRE S.; LEITE, VITOR B. P.. Probing Mastoparan-like Antimicrobial Peptides Interaction with Model Membrane Through Energy Landscape Analysis. Journal of Physical Chemistry B, v. 128, n. 1, p. 9-pg., 2023-12-30. (22/00347-0, 23/02219-1, 21/15028-4)