"Hit-to-lead" approach for the rational design of compounds against P. vivax hypnozoites

• Grant number: 24/14768-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Parasitology
• Principal Investigator: Carsten Wrenger
• Grantee: André Filipe Rivais Martins Barateiro
• Supervisor: Steven Patrick Maher
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Georgia, Athens (UGA), United States
• Associated to the scholarship: 23/08379-0 - Implementation of a human hepatocyte culture system to study the liver stages of the malaria parasites, BP.PD

Abstract

P. vivax is the primary cause of malaria outside Africa and an important, but often neglected, source of morbidity and mortality in endemic areas where the burden of P. falciparum malaria has been controlled. Public health strategies implemented to eliminate malaria in these areas affect both parasites unevenly due to specific biological differences between species. P. vivax has the important capacity to produce quiescent hypnozoites in the liver of patients who have cleared primary infection, which relapses initiate secondary infections without a new parasite inoculation by mosquito vectors. Commonly used therapies such as artemisinin-based therapies (ACTs) or even chloroquine are incapable of clearing quiescent hypnozoites in the liver. 8-aminoquinolines such as primaquine and tafenoquine are efficient in killing hypnozoites but with caveats. G6PD deficient patients cannot be treated with 8-aminoquinolines due to an important risk of developing severe hemolysis, while those with reduced levels of liver CYP2D6 enzyme fail to properly convert 8-aminonoquinolines into the by-products that have hypnozoitocidal activity. Therefore, continuous research and development of compounds with significant hypnozoitocidal activity is of utmost importance for the radical cure of P. vivax malaria. As such, we propose a "hit-to-lead" approach for the rational design of drugs with hypnozoitocidal activity, including the 1) high throughput screening and chemical modification of "hits" from a synthetic library using P. berghei and P. vivax liver stage in vitro assays, 2) validation and refinement of "leads" using P. cynomolgi liver stage in vitro assays, and 3) preclinical efficacy tests in P. cynomolgi-infected macaques.