Description
- Abstract:
- Malaria imposes an immense global health burden, and remains a significant driver of child mortality in sub-Saharan Africa. The emergence and spread of parasite strains resistant to artemisinin derivatives, the global first-line therapy, presents an imminent threat to public health. New antimalarials with novel mechanisms of action are desperately needed. This thesis details two preclinical studies supporting the development of 2741-19, a small-molecule drug discovered within the Kurtis Laboratory at the Center for International Health Research at Brown University. The compound is believed to target PfGARP, a parasite antigen expressed on the exofacial surface of infected trophozoite-stage erythrocytes. An in vitro selection for resistance study was performed to characterize the barrier to resistance of 2741-19 by establishing the minimum inoculum for resistance (MIR). Atovaquone was included as a positive control. Cultures of the Dd2 strain were seeded in triplicate with an inoculum of 3.85 × 109 parasites and maintained under continuous drug pressure at 3 × IC50 until recrudescence or for a maximum of 60 days. Selection for resistance to atovaquone was achieved, with recrudescence in all three replicates on day 28. Atovaquone-selected lineages exhibited a 10.5-fold increase in IC50 relative to the parental strain, validating the experimental design. In contrast, selection for resistance to 2741-19 yielded no resistant parasites, with no recrudescence observed through day 60. These results establish an MIR of > 9 for 2741-19, indicating an exceptionally high genetic barrier to resistance, comparable to chloroquine and artemisinin. Modified growth inhibition assays were also performed to characterize the compound’s pharmacodynamic profile. 2741-19 exhibited trophozoite-specific killing, which is consistent with PfGARP-mediated toxicity, the hypothesized mechanism of action. Maximum growth inhibition required slightly over 12 h of exposure. This demonstrates strong compatibility with the established 32–38 h elimination half-life, and reinforces the compound’s clinical viability as a prophylactic and therapeutic agent. Collectively, these findings position 2741-19 as a high-priority candidate for next-generation antimalarial development, driven by its robust genetic barrier to resistance and favorable pharmacodynamic profile.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
Chan, Michael,
"Characterization of the Novel Antimalarial 2741-19: Barrier to Resistance and Stage-Specific Activity"
(2026).
Biology and Medicine Theses and Dissertations, Biotechnology.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:7zj5v2vs/
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Biology and Medicine Theses and Dissertations
Theses and Dissertations for the Biology and Medicine department....