Last Updated: 31/07/2024
Study of enzyme kinetics and screening of compounds as candidates for inhibitors of the Plasmodium falciparum pyruvate kinase II (PKII) enzyme
Objectives
*Original in Portuguese: Estudo de cinética enzimática e triagem de compostos como candidatos a inibidores da enzima piruvato quinase II (PKII) de Plasmodium falciparum
Considering the importance of glycolytic enzymes in the parasite’s metabolism, as well as the need for new targets validated in P. falciparum for the development of drugs for malaria, this proposal aims to discover PfPKII inhibitors from collections made available by non-profit organization “Medicines for Malaria Venture” (MMV).
Malaria is a lethal parasite with worldwide prevalence and despite investments in the search for new therapies, a high mortality rate is still observed. In the search for new antimalarial drug candidates, modulation of the glycolytic pathway has been explored as a target to inhibit parasite development and combat infection. The Plasmodium falciparum pyruvate kinase II enzyme (PfPKII) is an attractive target of the parasite’s glycolytic pathway that catalyzes the conversion of phosphoenolpyruvate (PEP) and ADP into pyruvate and ATP. This enzyme is located in the parasite’s apicoplast and is essential for the functioning of the organelle, participating in processes involved in the biosynthesis of type II fatty acids. Preliminary results indicate that the standardized protocols were efficient for the soluble expression and purification of PfPKII with adequate purity for carrying out kinetic assays and biological screenings. Once the inhibitors have been identified, their inhibitory properties (IC50 values, Ki and inhibition mechanism) will be investigated for confirmation and validation as hits for the discovery of new candidates for lead compounds for malaria. Therefore, this research proposal will contribute to advancing the fight against malaria and the development of effective treatments for this devastating disease.
Oct 2023 — Jul 2024
