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

被引：61

作者：

Hameed, Shahul P. ^{[1
]}

Solapure, Suresh ^{[1
]}

Patil, Vikas ^{[1
]}

Henrich, Philipp P. ^{[2
]}

Magistrado, Pamela A. ^{[3
]}

Bharath, Sowmya ^{[1
]}

Murugan, Kannan ^{[1
]}

Viswanath, Pavithra ^{[1
]}

Puttur, Jayashree ^{[1
]}

Srivastava, Abhishek ^{[1
]}

Bellale, Eknath ^{[1
]}

Panduga, Vijender ^{[1
]}

Shanbag, Gajanan ^{[1
]}

Awasthy, Disha ^{[1
]}

Landge, Sudhir ^{[1
]}

Morayya, Sapna ^{[1
]}

Koushik, Krishna ^{[1
]}

Saralaya, Ramanatha ^{[1
]}

Raichurkar, Anandkumar ^{[1
]}

Rautela, Nikhil ^{[1
]}

Choudhury, Nilanjana Roy ^{[1
]}

Ambady, Anisha ^{[1
]}

Nandishaiah, Radha ^{[1
]}

Reddy, Jitendar ^{[1
]}

Prabhakar, K. R. ^{[1
]}

Menasinakai, Sreenivasaiah ^{[1
]}

Rudrapatna, Suresh ^{[1
]}

Chatterji, Monalisa ^{[1
]}

Belen Jimenez-Diaz, Maria ^{[4
]}

Santos Martinez, Maria ^{[4
]}

Maria Sanz, Laura ^{[4
]}

Coburn-Flynn, Olivia ^{[2
]}

Fidock, David A. ^{[2
,5
]}

Lukens, Amanda K. ^{[3
]}

Wirth, Dyann F. ^{[3
]}

Bandodkar, Balachandra ^{[1
]}

Mukherjee, Kakoli ^{[1
]}

McLaughlin, Robert E. ^{[6
]}

Waterson, David ^{[7
]}

Rosenbrier-Ribeiro, Lyn ^{[8
]}

Hickling, Kevin ^{[8
]}

Balasubramanian, V. ^{[1
]}

Warner, Peter ^{[1
]}

Hosagrahara, Vinayak ^{[1
]}

Dudley, Adam ^{[1
]}

Iyer, Pravin S. ^{[1
]}

Narayanan, Shridhar ^{[1
]}

Kavanagh, Stefan

Sambandamurthy, Vasan K. ^{[1
]}

机构：

[1] AstraZeneca India Pvt Ltd, Dept Innovat Med, Bangalore 560024, Karnataka, India

[2] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA

[3] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA

[4] GlaxoSmithKline, Dis Developing World, Madrid 28760, Spain

[5] Columbia Univ, Med Ctr, Dept Med, Div Infect Dis, New York, NY 10032 USA

[6] AstraZeneca Infect Innovat Med, Waltham, MA 02451 USA

[7] Int Ctr Cointrin, Med Malaria Venture, CH-1215 Geneva, Switzerland

[8] AstraZeneca, Alderley Pk SK10 4TF, Cheshire, England

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

美国国家卫生研究院;

关键词：

PLASMODIUM-FALCIPARUM; DRUG DISCOVERY; MALARIA PARASITE; PH REGULATION; H+-ATPASE; INHIBITION; MODELS; ASSAY;

D O I：

10.1038/ncomms7715

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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