Last Updated: 24/03/2025
Hit-to-lead approach for rational development of compounds against P. vivax hypnozoites
Objectives
*Original title in Portuguese: Abordagem “hit-to-lead” para o desenvolvimento racional de compostos contra hipnozoítos de P. vivax
This project aims to take a “hit-to-lead” approach for the rational design of drugs with hypnozoitocidal activity, including 1) large-scale screening and chemical modification of “hits” from a synthetic library using in vitro assays for the liver stages of P. berghei and P. vivax, 2) validation and refinement of “leads” using in vitro assays for the liver stage of P. cynomolgi, and 3) preclinical efficacy testing in P. cynomolgi-infected monkeys.
P. vivax is the leading cause of malaria outside Africa and is also associated with morbidity and mortality in endemic areas where P. falciparum malaria has been controlled. Public health strategies implemented to eliminate malaria in these areas affect the two parasites unequally due to species-specific biological differences. P. vivax has the ability to produce quiescent hypnozoites in the liver of patients who have cleared the primary infection, whose relapses initiate secondary infections in the absence of new parasite inoculation by vector mosquitoes. Commonly used treatments, such as artemisinin-containing combination therapy (ACTs) or even chloroquine, are unable to eliminate quiescent hypnozoites in the liver. The 8-aminoquinolines, such as primaquine and tafenoquine, are effective in killing hypnozoites, but with caveats. Patients with G6PD deficiency cannot be treated with 8-aminoquinolines due to a significant risk of severe hemolysis, while those with reduced levels of the hepatic enzyme CYP2D6 fail to adequately convert 8-aminoquinolines to the byproducts that have hypnozoitocidal activity. Therefore, continued research and development of compounds with potential hypnozoitocidal activity is important for the radical cure of P. vivax malaria.
Feb 2025 — Jan 2026
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