Inhibition of 3-Hydroxykynurenine Transaminase from Aedes aegypti and Anopheles gambiae: A Mosquito-Specific Target to Combat the Transmission of Arboviruses

Author(s)

Maciel, Larissa G. ; Ferraz, Matheus V. F. ; Oliveira, Andrew A. ; Lins, Roberto D. ; dos Anjos, Janaina V. ; Guido, Rafael V. C. ; Soares, Thereza A.

• Document type: Journal article
• Source: ACS BIO & MED CHEM AU; v. 3, n. 2, p. 12-pg., 2023-02-16.

Abstract

Arboviral infections such as Zika, chikungunya, dengue, and yellow fever pose significant health problems globally. The population at risk is expanding with the geographical distribution of the main transmission vector of these viruses, the Aedes aegypti mosquito. The global spreading of this mosquito is driven by human migration, urbanization, climate change, and the ecological plasticity of the species. Currently, there are no specific treatments for Aedes-borne infections. One strategy to combat different mosquito-borne arboviruses is to design molecules that can specifically inhibit a critical host protein. We obtained the crystal structure of 3-hydroxykynurenine transaminase (AeHKT) from A. aegypti, an essential detoxification enzyme of the tryptophan metabolism pathway. Since AeHKT is found exclusively in mosquitoes, it provides the ideal molecular target for the development of inhibitors. Therefore, we determined and compared the free binding energy of the inhibitors 4-(2-aminophenyl)-4-oxobutyric acid (4OB) and sodium 4-(3-phenyl-1,2,4-oxadiazol-5-yl)butanoate (OXA) to AeHKT and AgHKT from Anopheles gambiae, the only crystal structure of this enzyme previously known. The cocrystallized inhibitor 4OB binds to AgHKT with Ki of 300 mu M. We showed that OXA binds to both AeHKT and AgHKT enzymes with binding energies 2-fold more favorable than the crystallographic inhibitor 4OB and displayed a 2-fold greater residence time t upon binding to AeHKT than 4OB. These findings indicate that the 1,2,4-oxadiazole derivatives are inhibitors of the HKT enzyme not only from A. aegypti but also from A. gambiae. (AU)

• FAPESP's process: 20/12904-5 - Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays
• Grantee: Rafael Victorio Carvalho Guido
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 21/04283-3 - A multi-resolution approach to cation-induced polymorphism of lipopolysaccharide aggregates
• Grantee: Thereza Amélia Soares da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/07005-3 - Structural Biology and Medicinal Chemistry studies toward the discovery and design of new agrochemicals
• Grantee: Andrew Albert de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC