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

Paquet, Tanya and Le Manach, Claire and Cabrera, Diego González and Younis, Yassir and Henrich, Philipp P. and Abraham, Tara S. and Lee, Marcus C. S. and Basak, Rajshekhar and Ghidelli-Disse, Sonja and Lafuente-Monasterio, María José and Bantscheff, Marcus and Ruecker, Andrea and Blagborough, Andrew M. and Zakutansky, Sara E. and Zeeman, Anne-Marie and White, Karen L. and Shackleford, David M. and Mannila, Janne and Morizzi, Julia and Scheurer, Christian and Angulo-Barturen, Iñigo and Martínez, María Santos and Ferrer, Santiago and Sanz, Laura María and Gamo, Francisco Javier and Reader, Janette and Botha, Mariette and Dechering, Koen J. and Sauerwein, Robert W. and Tungtaeng, Anchalee and Vanachayangkul, Pattaraporn and Lim, Chek Shik and Burrows, Jeremy and Witty, Michael J. and Marsh, Kennan C. and Bodenreider, Christophe and Rochford, Rosemary and Solapure, Suresh M. and Jiménez-Díaz, María Belén and Wittlin, Sergio and Charman, Susan A. and Donini, Cristina and Campo, Brice and Birkholtz, Lyn-Marie and Hanson, Kirsten K. and Drewes, Gerard and Kocken, Clemens H. M. and Delves, Michael J. and Leroy, Didier and Fidock, David A. and Waterson, David and Street, Leslie J. and Chibale, Kelly. (2017) Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Science translational medicine, 9 (387). eaad9735.

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Official URL: http://edoc.unibas.ch/55098/

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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.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:	Scheurer, Christian
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	American Association for the Advancement of Science
ISSN:	1946-6234
Note:	Publication type according to Uni Basel Research Database: Journal article
Identification Number:	doi: 10.1126/scitranslmed.aad9735 pmid: 28446690
Last Modified:	06 Jun 2017 12:08
Deposited On:	06 Jun 2017 12:08

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