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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

AUTHORS

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

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. More... »

PAGES

6715

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ncomms7715

DOI

http://dx.doi.org/10.1038/ncomms7715

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016385194

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25823686


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