Isolation of novel antileishmanial molecules from Pentalinon andrieuxii root

描述（由申请人提供）：利什曼原虫是专性细胞内寄生虫，可引起广泛的疾病，如皮肤，粘膜和内脏利什曼原虫病。目前有1 200多万人患有这些疾病，每年约有200万人受到感染，使其成为一个重大的全球健康问题。皮肤利什曼病（CL）表现为局部皮肤病变，可愈合或成为慢性导致显著的组织破坏和毁容。显然有必要对CL进行局部治疗，因为目前对这种疾病的治疗涉及每天长时间注射锑类药物（GlucantimeTM或penttostamtm），这是有毒的，患者的依从性很差。在尤卡坦半岛，玛雅传统治疗师使用喷特利草根局部治疗利什曼病，这表明喷特利草根可能是治疗利什曼病的新型药物的潜在来源。在我们的初步研究中，我们已经发现对迭香根（PARE）的己烷提取物具有有效的抗利什曼原虫活性。我们的数据表明，PARE体外杀灭利什曼原虫的效率与葡聚糖metm一样高。PARE对哺乳动物细胞没有毒性，并能增加巨噬细胞的利什曼尼活性。本项目将寻求使用活性引导分离和标准分析方法（目标1）分离和表征PARE中的抗利什曼原虫化合物，并在小鼠和人巨噬细胞内测试其抗利什曼原虫活性（目标2）。我们假设PARE中的抗利什曼原虫分子对寄生虫发挥直接的细胞毒活性，并调节免疫细胞（如巨噬细胞）的活性。由于在利什曼病（Satoskar）和植物化学和天然产物开发（Kinghorn）方面的互补专业知识，我们的团队在开展这些研究方面具有独特的优势。我们的研究很重要，因为它们将在PARE中发现新的抗利什曼原虫分子，并为这些分子介导其活性的机制提供清晰的见解，这对未来的临床应用和药物开发至关重要。此外，这些研究将为这些分子增强巨噬细胞功能和利什曼尼活性的机制提供见解。总之，这些数据将为后来的RO1应用奠定基础，重点是更全面地研究pre衍生的活性成分在局部或全身治疗不同形式的利什曼病以及由其他锥虫病引起的疾病及其作用机制方面的作用。该项目的总体目标是从植物Pentalinon andrieuxii的根中分离和表征新的抗利什曼原虫化合物。

DESCRIPTION (provided by applicant): Leishmania are obligate intracellular parasites that cause a wide range of diseases such as cutaneous, mucocutaneous and visceral leishmaniasis. Over 12 million people currently suffer from these diseases, and approximately 2 million are infected annually, making this a major global health problem. Cutaneous leishmaniasis (CL) manifests as localized skin lesions which may heal or become chronic leading to significant tissue destruction and disfigurement. There is a clear need for a topical treatment against CL because current therapy for this disease involves daily injections of antimonials (GlucantimeTM or PentostamTM) for prolonged periods, which is toxic and has poor patient compliance. In the Yucatan Peninsula, Mayan traditional healers use Pentalinon andrieuxii root for topical treatment of CL, which suggests that P. andrieuxii can be a potential source of novel drugs to treat leishmaniasis. In our preliminary studies, we have found that hexane extract of Pentalinon andrieuxii root (PARE) exhibits potent antileishmanial activity. Our data indicate that PARE kills Leishmania in vitro as efficiently as GlucantimeTM. PARE is not toxic to mammalian cells and it also increases leishmanicidal activity in macrophages. This project will seek to isolate and characterize antileishmanial compound(s) in PARE using activity guided fractionation and standard analytical methods (Aim 1) and to test their leishmanicidal activity against intracellular Leishmania within mouse and human macrophages (Aim 2). We hypothesize that antileishmanial molecules in PARE exert direct cytotoxic activity against parasites as well as regulate activity of immune cells such as macrophages. Our team is uniquely poised to perform these studies due to complementary expertise in leishmaniasis (Satoskar), and phytochemistry and natural products development (Kinghorn). Our studies are important because they will identify novel antileishmanial molecules in PARE and provide clear insights into the mechanisms by which these molecules mediate their activity, which will be important for future clinical applications and drug development. In addition, these studies will provide insights into mechanisms by which these molecules enhance macrophage function and leishmanicidal activity. Together, these data will lay the foundation for a latter RO1 application focused on a more complete study of PARE-derived active components in local or systemic treatment of different forms of leishmaniasis as well as diseases caused by other trypanosomatids and their mechanism(s) of action. PUBLIC HEALTH RELEVANCE The overall goal of this project is to isolate and characterize novel anti-Leishmania compounds from the roots of plant Pentalinon andrieuxii.