Selective inhibitors of Heme Transporters as Antiparasitic Agents

作为抗寄生虫剂的血红素转运蛋白选择性抑制剂

• 批准号: 8901577
• 负责人: Iqbal Hamza
• 金额: $ 35.01万
• 依托单位: RAKTA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901577
• 关键词: Affect; Alleles; Animals; Antimony; Antiparasitic Agents; Area; Award; Bacterial Infections; Binding; Biochemical Pathway; Biological Assay; Biological Models; Biology; Budgets; Caenorhabditis elegans; Cells; Chemical Structure; Chemicals; Collaborations; Cutaneous; Cutaneous Leishmaniasis; Defect; Development; Disclosure; Disease; Dose; Drug Targeting; Drug Transport; Drug resistance; Effectiveness; Environment; Filarial Elephantiases; Future; Genetic Models; Goals; Growth; Growth and Development function; Health; Helminthiasis; Helminths; Heme; Hepatitis B; Hepatitis C; Homologous Gene; Human; Individual; Infection; International; Intestines; Iron; Lead; Legal patent; Leishmania; Leishmaniasis; Letters; Licensing; Life; Lymphatic; Malaria; Mammals; Maryland; Measures; Mediation; Metabolic Pathway; Metabolism; National Institute of Allergy and Infectious Disease; Nematoda; Nutrient; Onchocerciasis; Organism; Parasites; Parasitic Diseases; Parasitic infection; Parasitic nematode; Parasitology; Pathway interactions; Pharmaceutical Preparations; Phase; Physiological; Population; Process; Property; Relative (related person); Resistance development; Route; Schistosomiasis; Small Business Technology Transfer Research; Soil; Specificity; Staging; Technology; Therapeutic; Therapeutic Agents; Toxic effect; Trachoma; Trypanosoma; Trypanosomiasis; Tuberculosis; Universities; Visceral Leishmaniasis; Yeasts; alternative treatment; base; chemical stability; cofactor; cytotoxicity; drug development; drug metabolism; heme a; high throughput screening; in vivo; inhibitor/antagonist; innovation; killings; macrophage; mutant; neglect; neglected tropical diseases; novel; permease; phase 2 study; pre-clinical; programs; public health relevance; response; small molecule; success; transmission process; uptake; urban area

 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.

 描述（由适用提供）：包括蠕虫病和利什曼病在内的被忽视的热带疾病（NTD）是一组13个寄生虫和细菌感染，影响超过14亿人。尽管这些是全球关注的毁灭性疾病，但其相对于其他健康问题的被忽视状态导致治疗库有限 用于治疗的化合物。锥虫寄生虫L. major和L. Amazonesis分别是旧世界和新世界人类皮肤利什曼病的严肃特工。这两个物种结合在一起，每年估计有200万种新感染，约有3.5亿人居住在主动寄生虫传播区域中。在世界许多地区，利什曼病的治疗仍然依赖于有毒药物，例如五型锑，需要高剂量和冗长的治疗方法，而替代药物仍然是昂贵的，并且在内在地区不可广泛使用。这种情况，加上城市地区利什曼尼亚感染的最近增加，凸显了迫切需要鉴定这些生物体中基本途径的需求，这些途径可以由毒性较低的新药瞄准。该建议详细介绍了一条高度创新和跨学科的途径 与寄生虫生存的必需营养物质运输的途径 - 血红素 - 大多数寄生虫都需要从其环境中摄取。该理论策略是根据以下主要观察结果故意选择的：（a）血红素用于多个关键过程中； （b）在发展的所有阶段都需要血红素； （c）利什曼尼亚不能没有血红素并积极摄取它； （d）人类及其寄生虫都需要血红素，但是用于满足这一要求的机制是不同的。靶向血红素传输途径的药物是寄生虫独有的，而不是其哺乳动物宿主共享的药物具有巨大的治疗潜力。本应用中描述的研究将验证血红素转运蛋白 治疗利什曼原虫感染并提供新颖的化学物质的新靶标作为药物铅。 LHR1是血红素转运蛋白，对利什曼原虫的生存至关重要。单个LHR1等位基因（LHR1 +/-）的丧失会导致严重的生长，而LHR1 NULL突变体（LHR1 - / - ）并不可行，这表明LHR1功能降低了50％足以显着损害生长。在此I阶段ISTTR应用中，我们将（a）从LEISHMANIA的LHR1血红素转运蛋白进行结构完善并合成新型的小分子拮抗剂，评估这些新化合物在轴突膜膜的剂量反应生长中的效率，评估疗法的特异性，并测量促进性和血红素的特异性； （b）确定LHR1在亚马逊乳杆菌的细胞内膜片中的药物靶向的物理后果，它会引起皮肤利什曼病，并扩大我们对特定铅化合物的体内效率研究，以针对多诺万尼氏菌的细胞内膜膜膜的特定铅化合物，而多诺瓦氏菌（L.更广泛地说，该阶段I项目的成功将为动物的未来第二阶段研究和其他NTD的治疗奠定基础。