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Design and synthesis of ligands for PGK kinase to reduce Aedes aegypit development

Grant number: 22/11653-4
Support Opportunities:Scholarships in Brazil - Program to Stimulate Scientific Vocations
Effective date (Start): January 09, 2023
Effective date (End): February 28, 2023
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Vanderlan da Silva Bolzani
Grantee:Ana Beatriz Mestre Botelho
Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Arboviruses like dengue, zika and chikungunya have become a global health crisis. In Brazil, transmission of arboviruses by Aedes aegypit vector has profound impacts at the health system, where vaccines and drugs for these diseases are non-existent. The control of vector spreading by insecticides has been the most used way, but resistance by mosquitoes and toxicity to humans become those compounds less effective. To explore cellular pathways of the vector A. aegypti might result in innovative challenges for designing of insecticide candidates. The glycolytic pathway has been studied during the embryogenesis of A. aegypti, an energy cost mechanism for the embryo development. The glycolytic pathway is coordinated by protein kinases, such as phosphoglycerate kinase (PGK), which catalyzes 3-phosphoglycerate, an essential substrate for cellular ATP synthesis. The genome of A. aegypti was sequenced, but the validation of new therapeutic targets is uncovered addressing to lack of structural knowledge and gene functions. As a preliminary outcome, we built a 3D model for PGK of A. aegypti (AaPGK) based on the sequence of human PGK (hPGK), both with 70% similarity. Thus, we carried out molecular docking using hPGK inhibitors from the Published Kinase Inhibitor Set (PKIS) library; and then, we identified the compound A-674563 as AaPGK ligand, which by cellular assay, it reduced by 77% the development of A. aegypti larvae. Therefore, this research project aims to design and synthesize A-674563 derivatives as larval development inhibitors of A. aegypit vector. (AU)

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