Pre-Clinical Evaluation of Antimalarial Natural Products from Carica papaya L.

项目描述（由申请人提供）：该项目的长期目标是开发一种价格低廉、口服有效、无毒的治疗恶性疟原虫疟疾的新药（新化学实体[NCE]）。Radix Pharmaceuticals从番木瓜叶中分离纯化了两种天然产物，测定了两种化合物的化学结构。这些化合物对氯喹敏感型和耐药型疟疾菌株显示出同样有效的抑制活性。IC50（抑制50%的化合物浓度）优于阳性对照，氯喹和甲氟喹。这些化合物在成人肝上皮细胞和新分离的大鼠肝细胞中也显示出低毒性。此外，发现这些化合物具有理想的ADME（吸附、分布、代谢和排泄）特性。这些化合物具有干扰疟原虫色素合成的潜力，这是疟原虫不可缺少的过程。基于这些初步研究，这个I期项目的总体目标是建立候选药物的临床前概况。在第一阶段的支持下，我们将对这些化合物进行大规模的分离和纯化，并开始在啮齿动物模型中进行临床前研究，以获得功效、药代动力学和毒性数据。将进行以下互动研究，以高效和有效地获得啮齿动物的临床前资料：(I)将大规模分离和纯化两种天然产物（每种化合物1-2千克）。（二）将在感染人疟疾菌株的免疫功能低下的BXN小鼠和感染伯氏疟原虫啮齿动物疟疾菌株的雄性瑞士白化小鼠中获得抗疟效果数据。（III）试验化合物将通过静脉或口服给药给鼠，并计算药代动力学参数。（四）试验化合物将在啮齿动物模型中进行测试，以获得急性毒性、胎儿毒性、厌食毒性和神经毒性信息。在I期研究完成后，将选择具有口服活性且具有良好治疗指数的化合物进行II期进一步开发。II期的工作将包括在猕猴身上进行临床前研究，随后进行GMP分离/纯化和GLP评估。试验性新药（IND）申请将随后提交给FDA。公共卫生相关性：疟疾是世界上最常见的传染病之一。它每年影响约3亿人，导致200多万人死亡。前往中南美洲、非洲、亚洲（包括印度次大陆、东南亚和中东）、东欧和南太平洋的美国旅行者可能面临感染这种潜在致命疾病的风险。抗疟疾药物的市场每年有几亿美元。发现新的和有效的抗疟疾药物有可能对国家的经济和人民的健康作出重大贡献。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a new drug (new chemical entity [NCE]) that is inexpensive, orally active, non-toxic and can provide cure for P. falciparum malaria. Radix Pharmaceuticals has isolated and purified two natural products from the leaves of Carica papaya L. The chemical structures of both compounds were determined. These compounds showed equally potent inhibitory activity against both chloroquine sensitive and resistant malaria strains. The IC50's (concentration of compound that affords 50% of inhibition) were superior to the positive controls, chloroquine and mefloquine. These compounds also demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. Additionally, these compounds were found to possess desirable ADME (adsorption, distribution, metabolism, and excretion) characteristics. These compounds possess the potential to interfere hemozoin synthesis, an indispensable process for the malaria parasite. Based on these preliminary studies, the overall goal of this Phase I project is to establish pre-clinical profiles for the candidates. Under Phase I support, we will perform the scale up isolation and purification of these compounds and begin pre-clinical studies in rodent models to obtain efficacy, pharmacokinetics and toxicity data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (I) The two natural products will be isolated and purified in a larger scale (1-2 kg per compound). (II) Antimalarial efficacy data will be obtained in immunocompromised BXN mice infected with human malaria strains and male Swiss albino mice infected with rodent malaria strain P. berghei. (III) Test compounds will be administered intravenously or orally to rats and pharmacokinetic parameters will be calculated. (IV) Test compounds will be tested in rodent models to obtain acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. On completion of the Phase I studies, compound(s) that are orally active and possess good therapeutic index will be selected for further development in Phase II. The efforts in Phase II would include pre-clinical studies in Aotus monkey, followed by GMP isolation/purification and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA. PUBLIC HEALTH RELEVANCE: Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. American travelers to Central and South America, Africa, Asia (including the Indian Subcontinent, Southeast Asia, and the Middle East), Eastern Europe, and the South Pacific may be at risk for this potentially deadly disease. The market for anti-malarial drugs is a couple of hundred million dollars annually. Discovering new and effective anti-malarial drugs possesses potential to contribute significantly to the economy of the nation and to the health of her people.