Abstract：
Leishmaniasis is caused by ∼20 species of Leishmania that affects millions in endemic areas. Available therapies are not sufficient to effectively control the disease, cause severe side effects and eventually lead to drug resistance, making the discovery of novel therapeutic molecules an immediate need. Molecular target-based drug discovery, where the target is a defined molecular gene, protein or a mechanism, is a rationale driven approach for novel therapeutics. Humans obtain the essential amino acid such as threonine from dietary sources, while Leishmania synthesize it de-novo. Enzymes of the threonine biosynthesis pathway, including the rate limiting Homoserine kinase (HSK) which converts L-homoserine into ortho-phospho homoserine are thus attractive targets for rationale driven therapy. The absence of HSK in humans and its presence in Leishmania donovani enhances the opportunity to exploit HSK as a molecular target for anti-leishmanials therapeutic development. In this study, we utilize structure-based high throughput drug discovery (SBDD), followed by biochemical validation and identified two potential inhibitors (RH00038 and S02587) from Maybridge chemical library that targets L. donovani HSK. These two inhibitors effectively induced the mortality of Leishmania donovani in both amastigote and promastigote stages, with one of them being specific to parasite and twice as effective as the standard therapeutic molecule.
摘要：
利什曼病是由20种利什曼原虫引起的，在流行地区影响数百万人。现有的治疗方法不足以有效控制疾病,引起严重的副作用并最终导致耐药性，迫切需要发现新的治疗分子。基于分子靶标的药物发现，目标是一个确定的分子基因，蛋白质或机制，是新疗法的理论驱动方法。人类从膳食来源获得必需氨基酸如苏氨酸，而利什曼原虫是从头合成的。苏氨酸生物合成途径的酶，因此，包括将L-高丝氨酸转化为正磷酸高丝氨酸的限速高丝氨酸激酶（HSK）是理论驱动疗法的有吸引力的靶标。HSK在人类中的缺失及其在多尼利什曼原虫中的存在增加了利用HSK作为抗利什曼原虫治疗开发的分子靶标的机会。在这项研究中,我们利用基于结构的高通量药物发现(SBDD)，随后进行生化验证，并从Maybridge化学文库中鉴定出两种潜在的抑制剂（RH00038和S02587），靶向L.donovaniHSK。这两种抑制剂有效地诱导了利什曼原虫donovani的死亡在两个阶段的阿马斯蒂戈特和前乳突。其中一种对寄生虫具有特异性，是标准治疗分子的两倍。
