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DOI 10.1038/ncomms7715

Медицинская библиотека · Nature communications · 2015

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

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: 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. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.. Nature communications. 2015. DOI: 10.1038/ncomms7715.

Предметные рубрики MeSH

AminesAnimalsAntimalarialsDrug Evaluation, PreclinicalDrug Resistance, MicrobialGuinea PigsHalf-LifePlasmodium falciparumPyrimidinesRats
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