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
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Sci Transl Med. 2017 Apr 26;9(387). 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.
作为全球根除疟疾努力的一部分，表型全细胞筛选显示2-氨基吡啶类小分子是开发新型抗疟药物的良好起点。基于该系列研究，我们发现衍生物MMV390048与目前用于治疗疟疾的药物不存在交叉耐药性。该化合物对除肝脏中晚期休眠子之外的所有生命周期阶段均有效。在人源化小鼠模型中显示出了疗效，并且在小鼠模型中实现了小鼠间传播的适度降低。在猴子身上进行的实验表明MMV390048具有用于完全化学保护的能力。尽管MMV390048无法清除肝脏中的休眠子，但它在猴子模型中延迟了复发。基因组和化学蛋白质组学研究均确定疟原虫的一种激酶——磷脂酰肌醇4-激酶为MMV390048的分子靶点。MMV390048阻断疟原虫所有生命周期阶段的能力表明，该化合物应进一步开发，并且作为单剂量联合治疗的一部分，可能有助于疟疾的控制和根除。
