Publication: Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
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Date
2015
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Nature Pub. Group
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Hameed P., S., S. Solapure, V. Patil, P. P. Henrich, P. A. Magistrado, S. Bharath, K. Murugan, et al. 2015. “Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.” Nature Communications 6 (1): 6715. doi:10.1038/ncomms7715. http://dx.doi.org/10.1038/ncomms7715.
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Abstract
The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg−1 and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4–5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.
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