小柯机器人

2024年9月27日，美国加州大学河滨分校K. G. Le Roch等研究人员合作在《科学》杂志发表论文。该研究发现，kalihinol类似物破坏恶性疟原虫中的顶端体功能和囊泡运输。

研究人员报告了MED6-189的发现，这是一种kalihinol类异氰基萜类天然产物的类似物，对药物敏感和耐药的恶性疟原虫株均有效，能够阻止无性复制和性分化。体内研究使用人源化疟疾小鼠模型证实了该化合物在动物体内的高效性，且无明显的溶血活性或毒性。

互补的化学、分子和基因组分析显示，MED6-189靶向寄生虫顶端体，通过抑制脂质生物合成和细胞运输发挥作用。

遗传分析显示，PfSec13（编码寄生虫分泌机制的组成部分）中的突变降低了对该药物的敏感性。其高效力、出色的治疗特性以及独特的作用机制，使MED6-189成为抗疟药物研发管线中的重要补充。

附：英文原文

Title: A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria

Author: Z. Chahine, S. Abel, T. Hollin, G. L. Barnes, J. H. Chung, M. E. Daub, I. Renard, J. Y. Choi, P. Vydyam, A. Pal, M. Alba-Argomaniz, C. A. S. Banks, J. Kirkwood, A. Saraf, I. Camino, P. Castaneda, M. C. Cuevas, J. De Mercado-Arnanz, E. Fernandez-Alvaro, A. Garcia-Perez, N. Ibarz, S. Viera-Morilla, J. Prudhomme, C. J. Joyner, A. K. Bei, L. Florens, C. Ben Mamoun, C. D. Vanderwal, K. G. Le Roch

Issue&Volume: 2024-09-27

Abstract: We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

DOI: adm7966

Source: https://www.science.org/doi/10.1126/science.adm7966