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

Autor:	Hameed P S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Solapure S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Patil V; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Henrich PP; Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA., Magistrado PA; Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA., Bharath S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Murugan K; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Viswanath P; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Puttur J; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Srivastava A; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Bellale E; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Panduga V; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Shanbag G; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Awasthy D; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Landge S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Morayya S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Koushik K; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Saralaya R; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Raichurkar A; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Rautela N; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Roy Choudhury N; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Ambady A; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Nandishaiah R; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Reddy J; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Prabhakar KR; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Menasinakai S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Rudrapatna S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Chatterji M; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Jiménez-Díaz MB; Tres Cantos Medicines Development Campus. Diseases of Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Martínez MS; Tres Cantos Medicines Development Campus. Diseases of Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Sanz LM; Tres Cantos Medicines Development Campus. Diseases of Developing World (DDW), GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Coburn-Flynn O; Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA., Fidock DA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.; Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA., Lukens AK; Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA., Wirth DF; Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA., Bandodkar B; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Mukherjee K; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., McLaughlin RE; AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA., Waterson D; Medicines for Malaria Venture, International Center Cointrin, Geneva 1215, Switzerland., Rosenbrier-Ribeiro L; AstraZeneca, Alderley Park, Cheshire SK10 4TF, UK., Hickling K; AstraZeneca, Alderley Park, Cheshire SK10 4TF, UK., Balasubramanian V; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Warner P; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Hosagrahara V; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Dudley A; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Iyer PS; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Narayanan S; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India., Kavanagh S; AstraZeneca, Alderley Park, Cheshire SK10 4TF, UK., Sambandamurthy VK; Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2015 Mar 31; Vol. 6, pp. 6715. Date of Electronic Publication: 2015 Mar 31.
DOI:	10.1038/ncomms7715
Abstrakt:	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.
Databáze:	MEDLINE
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