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Title: KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission
Authors: Kelli L. Kuhen
Arnab K. Chatterjee
Matthias Rottmann
Kerstin Gagaring
Rachel Borboa
Jennifer Buenviaje
Zhong Chen
Carolyn Francek
Tao Wu
Advait Nagle
S. Whitney Barnes
David Plouffe
Marcus C.S. Lee
David A. Fidock
Wouter Graumans
Marga Van De Vegte-Bolmer
Geert J. Van Gemert
Grennady Wirjanata
Boni Sebayang
Jutta Marfurt
Bruce Russell
Rossarin Suwanarusk
Ric N. Price
Francois Nosten
Anchalee Tungtaeng
Montip Gettayacamin
Jetsumon Sattabongkot
Jennifer Taylor
John R. Walker
David Tully
Kailash P. Patra
Erika L. Flannery
Joseph M. Vinetz
Laurent Renia
Robert W. Sauerwein
Elizabeth A. Winzeler
Richard J. Glynne
Thierry T. Diagana
The Genomics Institute of the Novartis Research Foundation
Swiss Tropical and Public Health Institute (Swiss TPH)
Universitat Basel
Columbia University, College of Physicians and Surgeons
Radboud University Nijmegen Medical Centre
Menzies School of Health Research
Eijkman Institute for Molecular Biology
Agency for Science, Technology and Research, Singapore
Shoklo Malaria Research Unit
Mahidol University
Nuffield Department of Clinical Medicine
Armed Forces Research Institute of Medical Sciences, Thailand
University of California, San Diego
University of California, San Diego, School of Medicine
Novartis Institute for Tropical Diseases Pte. Ltd.
California Institute for Biomedical Research
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Jan-2014
Citation: Antimicrobial Agents and Chemotherapy. Vol.58, No.9 (2014), 5060-5067
Abstract: Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria. Copyright © 2014 Kuhen et al.
ISSN: 10986596
Appears in Collections:Scopus 2011-2015

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