Development of novel therapeutics for a neglected tropical disease leishmaniasis

开发新疗法治疗被忽视的热带疾病利什曼病

• 批准号: 8047041
• 负责人: Alan Douglas Kinghorn
• 金额: $ 262.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2013-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047041
• 关键词: Address; Afghanistan; Amphotericin B; Animal Model; Animals; Apoptosis; Area; Army Personnel; Aventis brand of meglumine antimoniate; Basic Science; Biological Testing; Canis familiaris; Chemicals; Clinical Research; Collaborations; Country; Cutaneous; Data; Development; Disease; Drug resistance; Foundations; Fractionation; Future; Goals; Hexanes; In Vitro; Industry; Infection; Institution; Iraq; Left; Leishmania; Leishmaniasis; Mammalian Cell; Mediating; Methods; Mexico; Miltefosine; Mus; Ohio; Parasite resistance; Parasites; Pentostam; Permeability; Pharmaceutical Preparations; Plant Components; Plant Roots; Plant Sources; Plants; Population; Preclinical Testing; Research Personnel; Resistance; Safety; Sand Flies; Secure; Source; Sterols; Synthesis Chemistry; The science of Mycology; Toxic effect; Translating; Tropical Disease; Universities; Visceral Leishmaniasis; Work; analog; compliance behavior; conventional therapy; endophytic fungi; fungus; global health; in vivo; killings; macrophage; membrane polarity; neglect; novel; novel therapeutics; obligate intracellular parasite; public health relevance; resistant strain; response; safety testing; stem; vector

DESCRIPTION (provided by applicant): This application in response to RFA-OD-10-005 addresses two thematic areas from the RFA, Global Health and Translating Basic Science Discoveries into New and Better Treatments. Transmitted by sand fly vectors, Leishmania are obligate intracellular parasites that cause a wide range of diseases, including cutaneous (CL), mucocutaneous (MCL) and visceral leishmaniasis (VL). Over 12 million people currently suffer from leishmaniasis, and approximately 2 million new cases occur each year, making it a major global health problem and a WHO classified neglected tropical disease. Recently, this disease is increasingly seen in canine populations in the US, as well as army personnel serving in Leishmania endemic countries such as Iraq and Afghanistan. Antimonials (Glucantime(tm) and Pentostam(tm)), amphotericin B, and miltefosine are used to treat leishmaniasis. Unfortunately these drugs are toxic and have poor patient compliance because many of them require systemic administration for periods ranging from 3-5 wks, and the emergence of drug-resistant strains is rapidly increasing worldwide. Therefore, there is a strong need for new drugs which are safe, cheap and easy to administer with broad-spectrum activity against different species of Leishmania. In the Yucatan Peninsula, Mayan traditional healers have used Pentalinon andrieuxii root for the topical treatment of CL for many years, indicating that P. andrieuxii contains antileishmanial molecules that could represent potential new drugs for leishmaniasis. We have found that a hexane extract of P. andrieuxii root (PARE) has potent antileishmanial activity both in vitro and in vivo. PARE kills Leishmania in vitro as efficiently as Glucantime(tm), and is also effective against intracellular parasites. Our preliminary data show that topical treatment with PARE is also effective in limiting L. mexicana infection in mice. Work on our ongoing R21 project (Isolation of novel antileishmanial molecules from Pentalinon andrieuxii Root; AI07639-01A1; A. Satoskar, investigator, A.D. Kinghorn, Co- investigator) has already led to the identification of several compounds with leishmanicidal activity in PARE, including two novel sterols. More bioactive molecules are expected to be isolated from the plant before the completion of this R21 project in August 2010. This application in response to RFA-OD-10-005 is to expand our ongoing studies and to undertake preclinical testing on antileishmanial molecules isolated from the plant P. andrieuxii and from fungi from Mycosynthetix Inc. In Aim 1, we will isolate antileishmanial molecules from the different components of the plant and identify their source(s). Aim 2 will use animal models to evaluate the safety and efficacy of these plant-derived molecules, as well as fungi-derived molecules, in treatment of different forms of leishmaniasis, as well as VL caused by parasites resistant to conventional drugs. Aim 3 will determine the mechanism(s) of action of molecules that are active in our animal studies. Our team is uniquely poised to perform the studies due to the complementary expertise in leishmaniasis (Satoskar), phytochemistry (Kinghorn), synthetic chemistry (Fuchs), and mycology/endophytic fungi (Pearce). Our studies should determine how bioactive molecules in P. andrieuxii mediate antileishmanial activity and provide information on their safety and efficacy to treat infections caused by Leishmania strains that are resistant to conventional treatment. Together these data will lay the foundation for advancing future clinical studies on these molecules for better treatment of various forms of leishmaniasis. PUBLIC HEALTH RELEVANCE: Infections caused by an intracellular protozoan parasite Leishmania are a major global health problem, and emergence of drug-resistant parasites is rapidly increasing world-wide. The overall goal of this project is to discover novel antileishmanial drugs from the plant Pentalinon andreuxii for treating different forms of leishmaniasis.

描述（由申请人提供）：此申请针对 RFA-OD-10-005，涉及 RFA 的两个主题领域：全球健康和将基础科学发现转化为新的更好的治疗方法。利什曼原虫由白蛉媒介传播，是专性细胞内寄生虫，可引起多种疾病，包括皮肤利什曼病 (CL)、皮肤粘膜利什曼病 (MCL) 和内脏利什曼病 (VL)。目前有超过 1200 万人患有利什曼病，每年约有 200 万新发病例，使其成为一个重大的全球健康问题，并被世界卫生组织列为被忽视的热带病。最近，这种疾病越来越多地出现在美国的犬类以及在伊拉克和阿富汗等利什曼原虫流行国家服役的军队人员中。锑剂（Glucantime(tm) 和 Pentostam(tm)）、两性霉素 B 和米替福辛用于治疗利什曼病。不幸的是，这些药物具有毒性并且患者依从性差，因为其中许多药物需要全身给药3-5周，并且全球范围内耐药菌株的出现正在迅速增加。因此，迫切需要安全、廉价、易于给药、对不同种类的利什曼原虫具有广谱活性的新药。在尤卡坦半岛，玛雅传统治疗师多年来一直使用 Pentalinon andrieuxii 根局部治疗 CL，这表明 P. andrieuxii 含有抗利什曼分子，可能是治疗利什曼病的潜在新药。我们发现 P. andrieuxii 根的己烷提取物 (PARE) 在体外和体内均具有有效的抗利什曼病活性。 PARE 在体外可以像 Glucantime(tm) 一样有效地杀死利什曼原虫，并且还可以有效对抗细胞内寄生虫。我们的初步数据表明，PARE 局部治疗也能有效限制小鼠体内墨西哥乳杆菌感染。我们正在进行的 R21 项目（从 Pentalinon andrieuxii Root 中分离新型抗利什曼原分子；AI07639-01A1；A. Satoskar，研究员，A.D. Kinghorn，联合研究员）的工作已经导致在 PARE 中鉴定出几种具有杀利什曼活性的化合物，包括两种新型甾醇。预计在 2010 年 8 月 R21 项目完成之前，将从该植物中分离出更多的生物活性分子。这项响应 RFA-OD-10-005 的申请旨在扩大我们正在进行的研究，并对从植物中分离出的抗利什曼尼分子进行临床前测试。植物 P. andrieuxii 和来自 Mycosynthetix Inc. 的真菌。在目标 1 中，我们将从植物的不同成分中分离出抗地利什曼尼分子，并鉴定它们的分子结构。来源。目标 2 将使用动物模型来评估这些植物衍生分子以及真菌衍生分子在治疗不同形式的利什曼病以及对传统药物产生耐药性的寄生虫引起的 VL 方面的安全性和有效性。目标 3 将确定在我们的动物研究中活跃的分子的作用机制。由于利什曼病 (Satoskar)、植物化学 (Kinghorn)、合成化学 (Fuchs) 和真菌学/内生真菌 (Pearce) 方面的互补专业知识，我们的团队具有独特的优势来开展这些研究。我们的研究应该确定安氏利什曼原虫中的生物活性分子如何介导抗利什曼原虫活性，并提供有关其治疗对常规治疗耐药的利什曼原虫菌株引起的感染的安全性和有效性的信息。这些数据将为推进这些分子的未来临床研究奠定基础，以更好地治疗各种形式的利什曼病。 公共卫生相关性：由细胞内原生动物寄生虫利什曼原虫引起的感染是一个主要的全球健康问题，并且全球范围内耐药寄生虫的出现正在迅速增加。该项目的总体目标是从植物 Pentalinon andreuxii 中发现新型抗利什曼病药物，用于治疗不同形式的利什曼病。

项目成果

Liposomal resiquimod for the treatment of Leishmania donovani infection.

脂质体瑞西莫德用于治疗杜氏利什曼原虫感染。

• DOI: 10.1093/jac/dkt320
• 发表时间: 2014
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Peine,KevinJ;Gupta,Gaurav;Brackman,DeannaJ;Papenfuss,TraceyL;Ainslie,KristyM;Satoskar,AbhayR;Bachelder,EricM
• 通讯作者: Bachelder,EricM