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）：本申请响应RFA-OD-10-005，涉及RFA的两个主题领域，即全球健康和将基础科学发现转化为新的更好的治疗方法。利什曼原虫是由白蛉传播的专性细胞内寄生虫，可引起多种疾病，包括皮肤（CL）、粘膜皮肤（MCL）和内脏利什曼病（VL）。目前有1 200多万人患有利什曼病，每年约有200万新病例，使其成为一个重大的全球健康问题，并被世卫组织列为被忽视的热带疾病。最近，这种疾病越来越多地出现在美国的犬群中，以及在利什曼原虫流行国家（如伊拉克和阿富汗）服役的军人中。锑剂（葡聚糖时间（TM）和戊糖醇（TM）），阿替霉素B，和米替福新用于治疗利什曼病。不幸的是，这些药物是有毒的，并且患者依从性差，因为它们中的许多需要全身给药3-5周的时间，并且耐药菌株的出现在世界范围内迅速增加。因此，迫切需要安全、廉价、易于给药且具有针对不同利什曼原虫物种的广谱活性的新药。在尤卡坦半岛，玛雅传统的治疗者多年来一直使用Pentalinon Pineuxii根局部治疗CL，这表明Pineuxii含有抗利什曼原虫分子，可能代表治疗利什曼病的潜在新药。我们已经发现，P. eucii根的己烷提取物（帕雷）在体外和体内都具有有效的抗利什曼原虫活性。帕雷在体外杀死利什曼原虫与Glucantime（tm）一样有效，并且对细胞内寄生虫也有效。我们的初步数据表明，局部治疗与帕雷也是有效的限制L。小鼠中的墨西哥线虫感染。我们正在进行的R21项目的工作（从Pentalinon penteuxii Root中分离新型抗利什曼原虫分子; AI 07639 - 01 A1; A. Satoskar，研究者，A.D. Kinghorn，共同研究者）已经导致鉴定了在帕雷中具有杀利什曼活性的几种化合物，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，并对从植物安德里亚青霉和Mycosynthetix Inc.的真菌中分离的抗利什曼原虫分子进行临床前测试。在目标1中，我们将从植物的不同组分中分离抗利什曼原虫分子并鉴定其来源。目标2将使用动物模型来评估这些植物来源的分子以及真菌来源的分子在治疗不同形式的利什曼病以及由对常规药物耐药的寄生虫引起的VL中的安全性和有效性。目标3将确定在我们的动物研究中具有活性的分子的作用机制。由于在利什曼病（Satoskar）、植物化学（Kinghorn）、合成化学（Fuchs）和真菌学/内生真菌（皮尔斯）方面的互补专业知识，我们的团队能够独一无二地进行研究。我们的研究应该确定P. pneumeuxii中的生物活性分子如何介导抗利什曼原虫活性，并提供有关其安全性和有效性的信息，以治疗对常规治疗有抗性的利什曼原虫菌株引起的感染。总之，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性健康问题，并且抗药性寄生虫的出现在世界范围内迅速增加。该项目的总体目标是从植物Pentalinon andreuxii中发现新的抗利什曼病药物，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