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.

项目总结和摘要 小分子靶向治疗利什曼原虫 利什曼病是一种被忽视的疾病，由利什曼原虫属寄生虫引起。 由白蛉媒介传播，并表现为不同的临床形式，包括皮肤溃疡、粘膜溃疡、 破坏，损害内脏器官，如肝脏和脾脏，以及骨髓损害。临床 结果主要取决于寄生虫的种类和宿主的免疫系统。有 98个国家受利什曼病影响，目前感染人数超过200万， 处于危险之中利什曼病的传播尤其令得克萨斯州等南部各州的美国公民担忧， 最近报告病例的俄克拉荷马州，以及驻扎在国外的美国军队， 地缘政治不稳定的地区，疾病往往会滋生。 利什曼病的化疗选择是有限的。几十年来，锑剂一直是一线药物 在大多数流行病的国家，尽管锑的不利影响是众所周知的， 抗锑寄生虫病例的增加。两性霉素B，主要的替代治疗，也会导致 严重的有害副作用。脂质体制剂的耐受性更好，但对于患者来说过于昂贵。 最受影响的人群。米替福新是一种抗癌药物，最近被重新用于治疗利什曼病， 是唯一一种在美国获得批准使用的口服治疗药物。米替福新也有毒性限制， 致畸性和缺乏对某些利什曼原虫属物种的效力。新化疗的发展 迫切需要治疗不同临床形式的利什曼病，这显然是一个未满足的医疗需求。 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 在加州大学圣地亚哥分校探索中心与Jair拉格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， 表征抗利什曼原虫小分子的活性，并将其开发为全身性和局部性的 治疗学该小组的初步工作已经导致了一种在体外具有纳摩尔浓度的化学型的鉴定。 对内脏和皮肤致病寄生虫的有效性，适当的药代动力学 用于体内研究，并在皮肤利什曼病感染模型中证明了体内功效。 这项资助概述了进一步发展化学型和解决特定挑战的建议， 抗利什曼病药物发现，包括药物靶点鉴定、给药和给药方案，以及 最重要的是该化学型治疗疾病的多种表现的适用性，包括那些 与美洲大陆最为相关和特有的疾病。我们的最终目标是至少开发一个预- 用于治疗内脏或皮肤利什曼病的临床候选者。