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

• Published in: Science translational medicine 2017-04, Vol.9 (387), p.eaad9735-eaad9735
• Main Authors: Paquet, Tanya, Le Manach, Claire, Cabrera, Diego González, Younis, Yassir, Henrich, Philipp P, Abraham, Tara S, Lee, Marcus C S, Basak, Rajshekhar, Ghidelli-Disse, Sonja, Lafuente-Monasterio, María José, Bantscheff, Marcus, Ruecker, Andrea, Blagborough, Andrew M, Zakutansky, Sara E, Zeeman, Anne-Marie, White, Karen L, Shackleford, David M, Mannila, Janne, Morizzi, Julia, Scheurer, Christian, Angulo-Barturen, Iñigo, Martínez, María Santos, Ferrer, Santiago, Sanz, Laura María, Gamo, Francisco Javier, Reader, Janette, Botha, Mariette, Dechering, Koen J, Sauerwein, Robert W, Tungtaeng, Anchalee, Vanachayangkul, Pattaraporn, Lim, Chek Shik, Burrows, Jeremy, Witty, Michael J, Marsh, Kennan C, Bodenreider, Christophe, Rochford, Rosemary, Solapure, Suresh M, Jiménez-Díaz, María Belén, Wittlin, Sergio, Charman, Susan A, Donini, Cristina, Campo, Brice, Birkholtz, Lyn-Marie, Hanson, Kirsten K, Drewes, Gerard, Kocken, Clemens H M, Delves, Michael J, Leroy, Didier, Fidock, David A, Waterson, David, Street, Leslie J, Chibale, Kelly
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 4-Kinase - antagonists & inhibitors; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Animals; Antimalarials - pharmacology; Antimalarials - therapeutic use; Female; Malaria - drug therapy; Malaria - enzymology; Male; Mice; Mice, SCID; Parasitic Sensitivity Tests; Plasmodium - drug effects; Plasmodium - pathogenicity; Plasmodium berghei; Plasmodium cynomolgi; Plasmodium falciparum; Sulfones - pharmacology; Sulfones - therapeutic use
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aad9735

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 life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the 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 monkey model. Both genomic and chemoproteomic studies identified a kinase of the 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.