Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
NATURE COMMUNICATIONS(2015)
摘要
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 ED 99 <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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关键词
Biological sciences, Chemical biology, Medicinal chemistry, Microbiology
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