Title : Characterizing the mechanism of action for antimalarial compound 2714-19
Abstract:
Malaria remains a major global health challenge, with an estimated 282 million cases and 610,000 deaths in 2024, according to the WHO World Malaria Report 2025. Plasmodium falciparum (P. falciparum) is the deadliest human malaria parasite. Although effective antimalarial drugs are available, the emergence and spread of drug resistance threaten their long-term effectiveness and highlight the urgent need for new antimalarial compounds with novel mechanisms of action.
The Kurtis Lab at Brown University has identified P. falciparum glutamic acid-rich protein (PfGARP) as a potential target for antimalarial intervention. PfGARP is an approximately 80 kDa protein expressed on the surface of infected erythrocytes and is increasingly expressed during the trophozoite stage. Our laboratory has shown that children lacking anti-PfGARP antibodies had a 2–5-fold higher risk of severe malaria, suggesting an important role for PfGARP in parasite survival.
Building on these findings, our laboratory screened a small-molecule library targeting PfGARP and identified compound 2741-19 as a lead antimalarial candidate. Compound 2741-19 inhibits P. falciparum 3D7 parasites in vitro, with an IC50 of approximately 40–100 nM, and activity has also been observed in ex vivo parasite samples from Kenya. ELISA studies demonstrated binding of 2741-19 to both recombinant and native PfGARP.
Ongoing studies are characterizing the mechanism of action of 2741-19, including potential signaling pathways and changes in parasite RNA levels. Defining its molecular mechanism may reveal a novel approach for targeting P. falciparum and contribute to the development of future antimalarial therapies capable of addressing drug resistance.
