KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

  • Antimicrob Agents Chemother. 2014 Sep;58(9):5060-7. doi: 10.1128/AAC.02727-13.
Kelli L Kuhen  1 ,  Arnab K Chatterjee  1 ,  Matthias Rottmann  2 ,  Kerstin Gagaring  1 ,  Rachel Borboa  1 ,  Jennifer Buenviaje  1 ,  Zhong Chen  1 ,  Carolyn Francek  1 ,  Tao Wu  1 ,  Advait Nagle  1 ,  S Whitney Barnes  1 ,  David Plouffe  1 ,  Marcus C S Lee  3 ,  David A Fidock  4 ,  Wouter Graumans  5 ,  Marga van de Vegte-Bolmer  5 ,  Geert J van Gemert  5 ,  Grennady Wirjanata  6 ,  Boni Sebayang  7 ,  Jutta Marfurt  6 ,  Bruce Russell  8 ,  Rossarin Suwanarusk  8 ,  Ric N Price  9 ,  Francois Nosten  10 ,  Anchalee Tungtaeng  11 ,  Montip Gettayacamin  11 ,  Jetsumon Sattabongkot  12 ,  Jennifer Taylor  1 ,  John R Walker  1 ,  David Tully  1 ,  Kailash P Patra  13 ,  Erika L Flannery  14 ,  Joseph M Vinetz  13 ,  Laurent Renia  8 ,  Robert W Sauerwein  5 ,  Elizabeth A Winzeler  15 ,  Richard J Glynne  1 ,  Thierry T Diagana  16
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation, San Diego, California, USA.
  • 2. Swiss Tropical and Public Health Institute, Parasite Chemotherapy, Basel, Switzerland University of Basel, Basel, Switzerland.
  • 3. Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
  • 4. Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York, USA Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
  • 5. Radboud University Nijmegen Medical Center, Medical Microbiology Department, Nijmegen, The Netherlands.
  • 6. Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia.
  • 7. Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
  • 8. Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research, Biopolis, Singapore.
  • 9. Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
  • 10. Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
  • 11. Department of Veterinary Medicine, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
  • 12. Entomology Department, AFRIMS, Bangkok, Thailand Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • 13. Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • 14. Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California, USA.
  • 15. Genomics Institute of the Novartis Research Foundation, San Diego, California, USA Division of Pharmacology and Drug Discovery, University of California, San Diego, School of Medicine, La Jolla, California, USA.
  • 16. Novartis Institute for Tropical Diseases, Singapore [email protected].
PMID: 24913172 DOI: 10.1128/AAC.02727-13
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.

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