Targeting the Genus Leishmania with Small Molecules

用小分子靶向利什曼原虫属

基本信息

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
项目类别：
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

项目摘要

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.

项目概要和摘要用小分子靶向利什曼原虫属利什曼病是一种被忽视的疾病，由利什曼原虫属原生动物寄生虫引起。由白蛉媒介传播，并以不同的临床形式表现，包括皮肤溃疡、粘膜破坏，对肝脏、脾脏等内脏器官的损害以及骨髓损害。结果主要取决于寄生虫的种类和宿主的免疫系统。 98个国家受利什曼病影响，目前感染人数超过200万人，感染人数达3.5亿利什曼病的传播尤其令得克萨斯州和德克萨斯州等南部各州的美国公民感到担忧。俄克拉荷马州最近报告了病例，以及驻扎在国外的美国军队地缘政治不稳定的地区是疾病容易流行的地区。几十年来，利什曼病的化疗选择有限。在大多数流行国家，尽管锑具有臭名昭著的不良影响，但住院要求和两性霉素 B（主要的替代治疗方法）的耐药性寄生虫病例的增加也是原因之一。脂质体制剂具有更好的耐受性，但价格昂贵。米替福辛是一种抗癌药物，最近被重新用于治疗利什曼病和米替福辛是美国唯一可用并批准使用的口服治疗药物，也有毒性限制，致畸性和对某些利什曼原虫缺乏疗效新化疗的开发。迫切需要治疗不同临床形式的利什曼病，而且显然是一个未得到满足的医疗需求。为了解决这一未满足的医疗需求，波士顿大学 (BU) 的 Scott Schaus 和 Lauren Brown 将与加州大学圣地亚哥分校探索中心的 Jair Lage Siqueira-Neto 领导一个合作项目寄生虫病创新 (CDIPD)，FIOCRUZ 的 Camila Indiani de Oliveira 和 BU 的 Mark Grinstaff 表征抗利什曼尼小分子的活性并将其开发为全身性和局部性该团队的初步工作已在体外鉴定出纳摩尔化学型。对内脏和皮肤致病寄生虫种类均有效，合适的药代动力学体内研究概况，并在皮肤利什曼病感染模型中证明了体内功效。这笔赠款概述了进一步开发化学型并解决具体挑战的提案抗利什曼病药物发现，包括药物靶标识别、剂量和给药选择，以及最重要的是化学型对于治疗疾病的多种表现的适用性，包括那些我们的最终目标是开发至少一种与美洲大陆最相关和流行的技术。用于治疗内脏或皮肤利什曼病的临床候选药物。