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Sci Transl Med. 2017 Apr 26;9(387). pii: eaad9735. doi: 10.1126/scitranslmed.aad9735.

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

Author information

1
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
2
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
3
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
4
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, Suite 368, Philadelphia, PA 19107, USA.
5
Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
6
Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520-8114, USA.
7
Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
8
Malaria Disease Performance Unit, Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
9
Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
10
Department of Parasitology, Biomedical Primate Research Centre, 2280 GH Rijswijk, Netherlands.
11
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
12
Admescope Ltd., Typpitie 1, 90620 Oulu, Finland.
13
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
14
University of Basel, 4003 Basel, Switzerland.
15
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria, South Africa.
16
TropIQ Health Sciences, Transistorweg 5, 6534 AT Nijmegen, Netherlands.
17
Radboud University Medical Center, Department of Medical Microbiology, 6500 HB Nijmegen, Netherlands.
18
Department of Veterinary Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand.
19
Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok 10400, Thailand.
20
Novartis Institute for Tropical Diseases Pte. Ltd., 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
21
Medicines for Malaria Venture, International Center Cointrin, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
22
AbbVie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA.
23
Departments of Immunology and Microbiology and Environmental and Occupational Health, University of Colorado Denver, Aurora, CO 80045, USA.
24
Nagarjuna Gardens, 60 Feet Road, Sahakaranagar, Bangalore 560092, India.
25
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas at San Antonio, 1 UTSA Circle, San Antonio, TX 78249, USA.
26
Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
27
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. kelly.chibale@uct.ac.za.
28
South African Medical Research Council Drug Discovery and Development Research Unit, and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.

Abstract

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.

PMID:
28446690
PMCID:
PMC5731459
DOI:
10.1126/scitranslmed.aad9735
[Indexed for MEDLINE]
Free PMC Article

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