Targeting the Genus Leishmania with Small Molecules

用小分子靶向利什曼原虫属

• 批准号: 10377374
• 负责人: Lauren Elaine Brown
• 金额: $ 76.42万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377374
• 关键词: Academia; Address; Adhesives; Adverse effects; Affect; Affinity; American; Amphotericin B; Antimony; Antineoplastic Agents; Antiparasitic Agents; Behavior; Biological Assay; Biology; Bone Marrow; Boston; Cells; Chemicals; Clinical; Collaborations; Country; Cutaneous; Cutaneous Leishmaniasis; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Exhibits; Experimental Models; Formulation; Genetic; Goals; Grant; Hospitalization; Immune system; In Vitro; Infection; Knock-out; Knowledge; Laboratories; Lead; Leishmania; Leishmania donovani; Leishmaniasis; Lesion; Liposomes; Liver; Medical; Methodology; Military Personnel; Miltefosine; Modeling; Molecular Target; Mucocutaneous leishmaniasis; Mucous Membrane; Mutation; Oklahoma; Oral; Organ; Organism; Outcome; Parasite resistance; Parasites; Parasitic Diseases; Parasitology; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Phlebotominae; Population; Reagent; Reporting; Research; Resistance; Risk; Route; Series; Skin; Spleen; Structure-Activity Relationship; Techniques; Teratogens; Testing; Texas; Therapeutic; Topical application; Toxic effect; Universities; Validation; Visceral; Visceral Leishmaniasis; Work; Yeasts; alternative treatment; analog; base; biocompatible polymer; chemotherapy; clinical candidate; cytotoxic; deep sequencing; design; drug candidate; drug discovery; ear infection; genome analysis; human disease; improved; in vivo; innovation; lead series; macrophage; member; monocyte; nanomolar; neglect; novel therapeutics; pre-clinical; programs; screening; side effect; skin ulcer; small molecule; vector

PROJECT SUMMARY AND ABSTRACT Targeting the Genus Leishmania with Small Molecules Leishmaniasis is a neglected disease caused by protozoan parasites from the genus Leishmania sp. It is transmitted by the sandfly vector and manifests in different clinical forms including skin ulcers, mucosa destruction, damage to visceral organs such as the liver and spleen, and bone marrow damage. The clinical outcome is determined primarily by the species of the parasite and the immune system of the host. There are 98 countries affected by leishmaniasis with more than 2 million people currently infected and 350 million people at risk. The spread of leishmaniasis is of particular concern to US citizens in southern states such as Texas and Oklahoma, where cases have recently been reported, as well as to US military troops stationed abroad in geopolitically unstable regions where the disease tends to thrive. Chemotherapy options for leishmaniasis are limited. Antimonials have been the first line drug for decades in most endemic countries, despite antimony’s notorious adverse effects, hospitalization requirements and increasing cases of antimony-resistant parasites. Amphotericin B, the main alternative treatment, also causes significant harmful side effects. Liposomal formulations are better tolerated, but are prohibitively expensive for most affected populations. Miltefosine, an anti-cancer drug, was recently repurposed to treat leishmaniasis and is the only oral treatment available and approved for use in the US. Miltefosine also has toxicity limitations, teratogenicity and lack of efficacy against certain Leishmania species. The development of new chemotherapies to treat the different clinical forms of leishmaniasis is in urgent demand, and is clearly an unmet medical need. To address this unmet medical need, Scott Schaus and Lauren Brown from Boston University (BU) will lead a collaborative project with Jair Lage Siqueira-Neto at the UC San Diego Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Camila Indiani de Oliveira at FIOCRUZ and Mark Grinstaff at BU to characterize the activity of antileishmanial small molecules and develop them as systemic and topical therapeutics. Preliminary work by the team has led to the identification of a chemotype with nanomolar in vitro efficacy against both visceral- and cutaneous-causative species of the parasite, a suitable pharmacokinetic profile for in vivo studies, and demonstrated in vivo efficacy in a cutaneous leishmaniasis infection model. This grant outlines a proposal to further develop the chemotype and address specific challenges in antileishmanial drug discovery, including drug target identification, options for dosing and administration, and most importantly the applicability of the chemotype to treat multiple manifestations of the disease, including those that are most relevant and endemic to the American continents. Our end goal is to develop at least one pre- clinical candidate for the treatment of either visceral or cutaneous leishmaniasis.

项目摘要和摘要 用小分子靶向利什曼原虫属 利什曼病是一种由利什曼原虫属的原生动物寄生虫引起的被忽视的疾病。它 由沙蝇载体传播，并以不同的临床形式表现出包括皮肤溃疡，粘膜 破坏，肝脏和脾脏等内脏器官的损害以及骨髓损伤。临床 结果主要取决于寄生虫的物种和宿主的免疫系统。有 98个国家受利什曼病影响的国家，目前有超过200万人感染了200万人和3.5亿人 有风险。利什曼病的传播特别关注美国南部各州的公民，例如德克萨斯州和 俄克拉荷马州最近有案件的报道，以及驻扎在国外的美国军队 疾病趋向于壮成长的地缘政治区域。 利什曼病的化学疗法选择有限。数十年来一直是第一行药物 在大多数情况下，目的地锑的臭名昭著的不良影响，住院要求和 增加了抗矛盾的寄生虫病例。两性霉素B（主要的替代方法）也会引起 重大有害副作用。脂质体配方的耐受性更好，但禁止昂贵 大多数受影响的人群。米尔特法辛（Miltefosine）是一种抗癌药物，最近被重新用于治疗利什曼病和 是唯一可在美国使用和批准使用的口服治疗方法。米尔特法辛还具有毒性限制， 对某些利什曼原虫物种的致病性和缺乏效率。新化学疗法的发展 治疗不同的利什曼病的临床形式是紧迫的需求，显然是未满足的医疗需求。 为了满足这种未满足的医疗需求，波士顿大学（BU）的Scott Schaus和Lauren Brown将 在圣地亚哥分校发现中心与Jair Lage Siqueira-Neto领导合作项目 Fiocruz的Camila Indiani de Oliveira的寄生疾病创新（CDIPD）和BU的Mark Grinstaff 表征抗精神小分子的活性，并将其发展为全身性和局部性 疗法。团队的初步工作导致识别体外纳摩尔的化学型 对寄生虫的内脏和皮肤促造成物种的功效，这是一种合适的药代动力学 体内研究的特征，并在皮肤利什曼病感染模型中证明了体内效率。 该赠款概述了进一步发展化学型并应对特定挑战的提议 抗精神病药发现，包括药物靶标识别，剂量和给药的选择，以及 最重要的是，化学型对治疗疾病多种表现的适用性，包括 与美洲大陆最相关和最重要的。我们的最终目标是发展至少一个 治疗内脏或皮肤利什曼病的临床候选者。