Isolation of novel antileishmanial molecules from Pentalinon andrieuxii root

描述(申请人提供)：利什曼原虫是一种专性细胞内寄生虫，可引起多种疾病，如皮肤、粘膜皮肤和内脏利什曼病。目前有超过1200万人患有这些疾病，每年约有200万人受到感染，这使其成为一个重大的全球健康问题。皮肤利什曼病(CL)是一种局部皮肤损害，可愈合或成为慢性疾病，导致严重的组织破坏和毁容。显然有必要对CL进行局部治疗，因为目前这种疾病的治疗方法是每天长时间注射锑(GLucantimeTM或PentostaTM)，这是有毒的，患者依从性很差。在尤卡坦半岛，玛雅人的传统治疗师使用五倍子的根来局部治疗CL，这表明五倍子可以成为治疗利什曼病的新药物的潜在来源。在我们的初步研究中，我们发现五倍子正己烷提取物(PAE)具有很强的抗利什曼活性。我们的数据表明，PARE在体外对利什曼原虫的杀灭效果与GLucantimeTM一样有效。PARE对哺乳动物细胞无毒，还可增加巨噬细胞的利什曼杀菌活性。本项目将寻求利用活性导向分离和标准分析方法(目标1)分离和鉴定PARE中的抗利什曼化合物(S)，并测试它们在小鼠和人巨噬细胞中对细胞内利什曼原虫的杀灭活性(目标2)。我们假设PARE中的抗利什曼分子对寄生虫具有直接的细胞毒活性，并调节巨噬细胞等免疫细胞的活性。由于在利什曼病(Satoskar)以及植物化学和天然产品开发(Kinghorn)方面的专业互补，我们的团队准备进行这些研究。我们的研究很重要，因为它们将在PARE中发现新的抗利什曼分子，并为这些分子调节其活性的机制提供清晰的见解，这将对未来的临床应用和药物开发具有重要意义。此外，这些研究将为这些分子增强巨噬细胞功能和杀利什曼活性的机制提供洞察力。总之，这些数据将为后面的RO1应用奠定基础，该应用侧重于在不同形式的利什曼病以及其他锥虫引起的疾病及其作用机制的局部或系统治疗中更完整地研究PARE衍生的活性成分(S)。与公共卫生相关本项目的总体目标是从植物五羟色胺的根中分离和鉴定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.