Targeting the Genus Leishmania with Small Molecules

项目摘要和摘要 用小分子靶向利什曼原虫属 利什曼病是由利什曼原虫引起的一种被忽视的疾病。它 通过沙蝇媒介传播，并以不同的临床形式表现，包括皮肤溃疡、粘膜 破坏，损害内脏器官，如肝和脾，以及骨髓损害。临床部 结果主要取决于寄生虫的种类和宿主的免疫系统。确实有 98个国家受利什曼病影响，目前有200多万人感染，3.5亿人 处于危险之中。利什曼病的传播尤其令德克萨斯州和德克萨斯州等南部州的美国公民担忧 俄克拉荷马州，最近报告了病例，以及驻扎在海外的美军 地缘政治不稳定的地区，疾病往往在这些地区蓬勃发展。 利什曼病的化疗选择有限。几十年来，锑一直是第一线药物。 在大多数流行疾病的国家，尽管锑的不良影响臭名昭著，但住院要求和 越来越多的抗锑寄生虫病例。两性霉素B是主要的替代治疗方法，也会导致 显著的有害副作用。脂质体制剂耐受性较好，但对于 受影响最大的人群。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 是美国唯一可用并被批准使用的口腔治疗方法。米替福辛也有毒性限制， 对某些利什曼原虫的致畸性和缺乏效力。新化疗药物的发展 治疗不同临床形式的利什曼病是迫切需要的，显然是一种未得到满足的医疗需求。 为了解决这一未得到满足的医疗需求，波士顿大学(BU)的斯科特·肖斯和劳伦·布朗将 与加州大学圣地亚哥分校发现中心的Jair Lage Siqueira-Neto共同领导一个合作项目 寄生虫病创新(CDIPD)，Fiocruz的Camila Indiani de Oliveira和BU To的Mark Grinstaff 表征抗利什曼病小分子的活性，并将其发展为系统性和局部性的 治疗学。该团队的初步工作导致在体外鉴定出一种具有纳米分子的化学类型 对内脏和皮肤引起的寄生虫的疗效，合适的药代动力学 用于体内研究的概况，并在皮肤利什曼病感染模型中证明了体内疗效。 这笔赠款概述了一项建议，以进一步开发化学类型和解决具体的挑战 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，化学分型对治疗多种疾病表现的适用性，包括 它们是美洲大陆最相关和最地方性的。我们的最终目标是开发至少一个预 内脏或皮肤利什曼病的临床候选治疗。

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.