Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate
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Hameed P., Shahul
Solapure, Suresh
Patil, Vikas
Henrich, Philipp P.
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.
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.
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https://doi.org/10.1038/ncomms7715Metadata
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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.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389225/pdf/Terms of Use
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