Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate

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Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate

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Title: Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
Author: Hameed P., Shahul; Solapure, Suresh; Patil, Vikas; Henrich, Philipp P.; Magistrado, Pamela A.; Bharath, Sowmya; Murugan, Kannan; Viswanath, Pavithra; Puttur, Jayashree; Srivastava, Abhishek; Bellale, Eknath; Panduga, Vijender; Shanbag, Gajanan; Awasthy, Disha; Landge, Sudhir; Morayya, Sapna; Koushik, Krishna; Saralaya, Ramanatha; Raichurkar, Anandkumar; Rautela, Nikhil; Roy Choudhury, Nilanjana; Ambady, Anisha; Nandishaiah, Radha; Reddy, Jitendar; Prabhakar, K. R.; Menasinakai, Sreenivasaiah; Rudrapatna, Suresh; Chatterji, Monalisa; Jiménez-Díaz, María Belén; Martínez, María Santos; Sanz, Laura María; Coburn-Flynn, Olivia; Fidock, David A.; Lukens, Amanda K.; Wirth, Dyann F.; Bandodkar, Balachandra; Mukherjee, Kakoli; McLaughlin, Robert E.; Waterson, David; Rosenbrier-Ribeiro, Lyn; Hickling, Kevin; Balasubramanian, V.; Warner, Peter; Hosagrahara, Vinayak; Dudley, Adam; Iyer, Pravin S.; Narayanan, Shridhar; Kavanagh, Stefan; Sambandamurthy, Vasan K.

Note: Order does not necessarily reflect citation order of authors.

Citation: 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.
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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.
Published Version: doi:10.1038/ncomms7715
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