Description
- Abstract:
- Introduction: Malaria, caused by the Plasmodium parasite, is a leading cause of mortality in sub-Saharan Africa, disproportionately affecting children under the age of 5. The species Plasmodium falciparum is responsible for > 95% of these deaths. Recent spread of drug resistance in Africa to the mainstays of malaria treatment, artemisinin combination therapy (ACT), underscores the importance of novel antimalarial compound development. The Kurtis Lab at Brown University previously identified families of antimalarial small-molecule compounds believed to target P. falciparum glutamic acid rich protein (PfGARP). 2741-19 is the most effective compound with an IC50 around 50 nM. Part II investigates 2741-19 drug binding with P. falciparum proteins to support mounting evidence that 2741-19 kills P. falciparum via PfGARP binding, an independent mechanism of action from artemisinin derivatives and ACT partner drugs. Part III assesses the potential for in vitro synergistic killing of P. falciparum between short acting 2741-19 and longer lasting ACT partner drugs widely used in Africa, lumefantrine and piperaquine. Methods: Drug binding enzyme-linked immunosorbent assays (ELISA) were performed over 72 hours examining binding between a variety of Plasmodium proteins and antimalarial compounds. Growth inhibition assays designed with dose-response matrix dilutions were conducted and four mathematical models (i.e., ZIP, HSA, Loewe Additivity, Bliss Independence) were utilized to assess in vitro synergistic killing. Results: 2741-19 showed over 4X higher binding to PfGARP via optical density (OD) measurements than other antimalarials and statistical significance compared to controls (p < 0.0001). 2741-19 and piperaquine synergistically kill P. falciparum in vitro across relevant synergy models, with highest scoring in the Bliss Independence model. Conclusions: Differential binding of 2741-19 to PfGARP in ELISAs is consistent with 2741-19 binding to PfGARP in its mechanism of killing action, unique from current clinically utilized antimalarials. Highest in vitro synergy scoring with piperaquine in the Bliss Independence model supports the notion that these compounds operate on unique pathways to inhibit P. falciparum growth and proliferation. These findings support further evaluation of 2741-19 and piperaquine as promising candidates for the next generation of antimalarial combination treatments.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
Skinner, Brooke,
"2741-19 in combination with piperaquine as next generation therapy against P. falciparum"
(2026).
Biotechnology, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:6akjd6b6/
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Biology and Medicine Theses and Dissertations
Theses and Dissertations for the Biology and Medicine department....