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Development of Novel Natural Product Inspired Antileishmanial Drugs

受天然产物启发的新型抗利什曼药物的开发

基本信息

批准号：
10382455
负责人：
Scott M Landfear
金额：
$ 18.96万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-02 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382455
关键词：
Alkaloids Antiparasitic Agents Biological Availability Cellular biology Clinical Trials Collaborations Communicable Diseases Cutaneous Cutaneous Leishmaniasis Cytostatics Data Dependence Development Disease Disease model Dose Drug Kinetics Drug resistance Drug usage Exhibits Goals Growth Growth Inhibitors Hand In Vitro Inbred BALB C Mice Individual Infection Infection Control Intraperitoneal Injections Knowledge Laboratories Lead Leishmania Leishmania donovani Leishmania mexicana Leishmaniasis Luciferases Malaria Mammalian Cell Measures Metabolic Microsomes Molecular Biology Monitor Mus Natural Products Oral Parasites Pathology Persons Pharmaceutical Chemistry Pharmaceutical Preparations Plasmodium yoelii Predisposition Property Resource-limited setting Solubility Structure-Activity Relationship Testing Therapeutic Therapeutic Index Time Toxic effect Visceral Leishmaniasis World Health Organization analog aqueous cytotoxic drug development drug testing efficacy testing experimental study improved in vivo innovation intraperitoneal macrophage mouse model neglect novel novel therapeutics parenteral administration physical property preclinical study response scaffold

项目摘要

SUMMARY Leishmania and other kinetoplastid parasites cause devastating diseases that afflict millions of people, yet current antileishmanial therapies are woefully inadequate, suffering from toxicity, difficulty of delivery, development of drug resistance, poor efficacy, etc. Hence, there is a widely recognized and urgent need for development of novel therapies that represent improvements over current drugs. This proposal will explore the potential of the natural product-derived tambjamines as potential novel drug leads against leishmaniasis. Tambjamines and structurally related compounds are potent inhibitors of growth of malaria parasites in vivo in murine models of malaria, with some of them being curative when delivered as a single oral dose. Initial experiments with 106 structurally diverse pyrrolylpyrromethene alkaloid analogs identified 26 tambjamines with 30-100 nM EC50 values for growth inhibition of Leishmania mexicana and L. donovani amastigotes growing inside mammalian macrophages and in vitro therapeutic indices >10, making this class of compounds almost 2 orders of magnitude more potent that current antileishmanial drugs and thus promising candidates for development of new orally bioavailable drugs for use against these parasites. In this proposal, novel tambjamines will be synthesized with expected improved properties for in vivo efficacy, including superior metabolic stability, increased aqueous solubility for improved oral bioavailability, and decreased toxicity. In vitro and in vivo pharmacokinetic properties will be determined for new tambjamines, and the most promising analogs will be tested for efficacy in controlling both cutaneous leishmaniasis induced by L. mexicana and fatal visceral leishmaniasis caused by L. donovani in murine models of these diseases. The overall objective is to advance tambjamines to the level of compounds that are active against Leishmania parasites in vivo so that they can be further developed as novel, potent, orally bioavailable leads toward new antileishmanial drugs.

总结利什曼原虫和其他动质体寄生虫引起的毁灭性疾病折磨着数百万人，目前的抗利什曼病疗法严重不足，存在毒性，难以递送，耐药性的发展，疗效差等。因此，有一个广泛认识和迫切需要，开发新的治疗方法，代表对现有药物的改进。本提案将探讨天然产物衍生的坦比贾明作为潜在的抗利什曼病新药的潜力。坦布贾明和结构相关的化合物是体内疟原虫生长的有效抑制剂，小鼠疟疾模型，其中一些在作为单次口服剂量递送时具有治愈性。初始用106种结构不同的吡咯基吡咯亚甲基生物碱类似物进行的实验鉴定了26种tambjamines，墨西哥利什曼原虫和L. Donovani无鞭毛体生长在哺乳动物巨噬细胞内和体外治疗指数>10，使得这类化合物几乎为2 比目前的抗利什曼病药物更有效的数量级，因此有希望成为开发用于对抗这些寄生虫的新的口服生物可利用药物。在这篇文章中，小说将合成具有预期的改善的体内功效性质的坦比贾明，包括上级代谢稳定性、增加的水溶性以改善口服生物利用度和降低的毒性。体外和体内药代动力学特性将被确定为新的tambjamines，和最有前途的将测试类似物在控制由L.墨西哥和致命内脏利什曼病由L. donovani在这些疾病的小鼠模型中的作用。总体目标是将坦比贾明提高到在体内对利什曼原虫有活性的化合物的水平，它们可以进一步开发为新的、有效的、口服生物可利用的抗利什曼病药物的先导物。