Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Nature communications, 2015-03, Vol.6 (1), p.6715-6715, Article 6715

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. The emergence of resistant Plasmodium strains fuels the search for new antimalarials. Here, the authors present a new class of potent antimalarial compounds, the triaminopyrimidines, that display low toxicity and long half-life in animal models.