Selective inhibitors of Heme Transporters as Antiparasitic Agents

 描述（由申请人提供）：被忽视的热带病（NTD），包括蠕虫病和利什曼病，是一组13种寄生虫和细菌感染，影响超过14亿人。虽然这些是全球关注的毁灭性疾病，但相对于其他健康问题而言，它们被忽视的地位导致治疗手段有限。 化合物用于治疗。锥虫L. major和L.亚马逊黑热病分别是旧大陆和新大陆人类皮肤利什曼病的病原体。这两个物种加在一起，估计每年有200万新感染，约3.5亿人生活在活跃的寄生虫传播地区。在世界许多地区，治疗利什曼病仍然依赖五价锑等有毒药物，这需要高剂量和漫长的疗程，替代药物仍然昂贵，在流行地区并不普遍。这种情况，加上最近在城市地区利什曼原虫感染的增加，突出了迫切需要确定这些生物体中的基本途径，可以通过新的药物具有较低的毒性。该提案详细介绍了一条高度创新和跨学科的路线， 拮抗运输寄生虫生存所必需的营养物质-血红素-的途径，大多数寄生虫需要从环境中摄取血红素。这种治疗策略是基于以下关键观察而故意选择的：（a）血红素用于多个关键过程;（B）血红素在发育的所有阶段都是必需的;（c）利什曼原虫不能在没有血红素的情况下生存，并主动摄取它;以及（d）人类及其寄生虫都需要血红素，但用于满足这一要求的机制不同。因此，针对寄生虫特有的血红素转运途径而不是其哺乳动物宿主所共有的药物提供了巨大的治疗潜力。本申请中描述的研究将验证血红素转运蛋白作为 治疗利什曼原虫感染的新靶点，并提供作为药物先导物的新化学物质。LHR 1是一种血红素转运蛋白，对利什曼原虫的生存至关重要。单个LHR 1等位基因（LHR 1 +/-）的缺失导致严重的生长缺陷，而LHR 1无效突变体（LHR 1-/-）是不能存活的，这表明LHR 1功能降低50%足以显著损害生长。在该I期STTR申请中，我们将（a）从结构上改进和合成利什曼原虫LHR 1血红素转运蛋白的新型小分子拮抗剂，评价这些新型化合物在无鞭毛体的剂量-反应生长中的功效，评估拮抗作用的特异性，并测量血红素转运抑制;和（B）确定利什曼原虫细胞内无鞭毛体中LHR 1的药理学靶向的生理后果。amazonensis，它会导致皮肤利什曼病，并扩大我们的体内疗效研究的特定铅化合物对细胞内无鞭毛体的L。donovani，更致命的内脏利什曼病的病原体，在初级巨噬细胞。更广泛地说，这个第一阶段项目的成功将为未来的第二阶段动物研究和其他NTD的治疗奠定基础。

 DESCRIPTION (provided by applicant): Neglected Tropical Diseases (NTD), which include helminthiasis and leishmaniasis, are a group of thirteen parasitic and bacterial infections that affect over 1.4 billion people. Although these are devastating diseases of global concern, their neglected status relative to other health concerns has resulted in a limited arsenal of therapeutic compounds for their treatment. The trypanosomatid parasites L. major and L. amazonensis are causative agents of human cutaneous leishmaniasis in the Old World and New World, respectively. Combined, these two species are responsible for an estimated 2 million new infections annually with ~350 million people living in areas of active parasite transmission. In many regions of the world, treatment of leishmaniasis still relies on toxic drugs such as pentavalent antimony, which requires high doses and lengthy courses of treatment, and alternative drugs are still costly and not widely available in endemic areas. This situation, combined with the recent increase in Leishmania infections in urban areas, highlights the urgent need for identification of essential pathways in these organisms that can be targeted by new drugs with lower toxicity. This proposal details a highly innovative and interdisciplinary route to antagonize pathways for the transport of an essential nutrient for parasite survival - heme - which most parasites need to ingest from their environment. This therapeutic strategy was deliberately chosen based on the following key observations: (a) heme is utilized in multiple, critical processes; (b) heme is required in all stages of development; (c) Leishmania cannot live without heme and actively ingest it; and (d) both humans and their parasites require heme, but the mechanisms used to fulfill this requirement are different. Thus drugs that target heme transport pathways unique to the parasite and not shared by its mammalian host offers great therapeutic potential. The studies described in this application will validate heme transporters as novel targets for treating Leishmania infections and provide novel chemical matter as drug leads. LHR1 is a heme transporter that is essential for Leishmania survival. Loss of a single LHR1 allele (LHR1+/-) causes severe growth defects while LHR1 null mutants (LHR1-/-) are not viable suggesting that a 50% reduction in LHR1 function is sufficient to significantly impair growth. In this Phase I STTR application, we will (a) structurally refine and synthesize novel small molecule antagonists of LHR1 heme transporter from Leishmania, evaluate the efficacy of these novel compounds in dose-response growth of axenic amastigotes, assess the specificity of antagonism, and measure heme transport inhibition; and (b) determine the physiological consequences of pharmacologic targeting of LHR1 in intracellular amastigotes of L. amazonensis, which causes cutaneous leishmaniasis, and expand our in vivo efficacy studies of specific lead compounds against intracellular amastigotes of L. donovani, the causative agent of the more fatal visceral Leishmaniasis, in primary macrophages. More broadly, the success of this Phase I project will lay the groundwork for future Phase II studies in animals and for the treatment of other NTD.