Investigation of Plasmodium falciparum apicoplast enzymes as molecular targets for the discovery of leading compounds for malaria.

• Grant number: 24/21167-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2025
• End date: July 31, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: João Pedro Salazar Martins
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Malaria remains one of the most prevalent infectious diseases globally, with high incidence and mortality rates. The emergence of Plasmodium falciparum strains resistant to primary antimalarial drugs is concerning and compromises the effectiveness of current treatments. This underscores the need for innovative therapies targeting new biological mechanisms. The apicoplast, a unique and essential organelle in the parasite, has attracted interest due to its lack of an equivalent in human cells, making its enzymes promising targets for selective antimalarial inhibitors. In this proposal, we focus on the enzymes pyruvate kinase II (PfPKII) and DOXP synthase (PfDXPS) as potential molecular targets for lead compound discovery. These enzymes play crucial roles in maintaining apicoplast homeostasis, and their inhibition significantly disrupts parasite metabolism. Using a multidisciplinary approach that combines X-ray crystallography, cryo-electron microscopy, biochemistry, molecular modeling, and medicinal chemistry, this project aims to evaluate PfPKII and PfDXPS as viable targets for the development of novel antimalarial inhibitors. These studies are critical to advancing malaria treatment strategies and addressing the challenge of drug-resistant P. falciparum.