Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics.
Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics.
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DOI：
10.1093/nar/gkv821
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发表时间：
2015-09-30
影响因子：
14.9
通讯作者：
Baasov T
中科院分区：
文献类型：
--
作者：
Shalev M;Rozenberg H;Smolkin B;Nasereddin A;Kopelyanskiy D;Belakhov V;Schrepfer T;Schacht J;Jaffe CL;Adir N;Baasov T
利什曼病包括由致病性利什曼原虫引起的一系列疾病，导致一系列轻微至危及生命的病理。目前可用的利什曼病治疗方法包括有限的药物选择。再加上寄生虫耐药性的迅速出现，构成了一个可怕的公共卫生问题。帕罗霉素（Paromomycin， PAR）是一种广谱氨基糖苷类抗生素，近年来被证明在治疗内脏利什曼病（VL）——一种危及生命的疾病——方面非常有效。虽然对PAR在细菌中的活性进行了大量的研究，但其在利什曼原虫中的作用机制却很少受到审查，而且尚未完全破译。在本研究中，我们提出了PAR与rRNA结合的x射线结构模型，模拟其利什曼结合靶点，核糖体a位点。通过比较几种结构相关的天然和合成氨基糖苷衍生物，我们还评估了PAR对利什曼动物生长和核糖体功能的抑制作用，以及对听觉细胞的影响。这些结果为氨基糖苷对利什曼细胞质核糖体的抑制活性和选择性提供了重要的结构元件，突出了一种新的合成衍生物，化合物3，作为治疗VL的前瞻性候选药物。
Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)—the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3, as a prospective therapeutic candidate for the treatment of VL.