Effects of Artemisinin on Leishmania SERCA pump

青蒿素对利什曼原虫SERCA泵的影响

基本信息

批准号：
7454321
负责人：
JOHN CHRISTOPHER MEADE
金额：
$ 7.26万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7454321
关键词：
Adverse effects Africa South of the Sahara African Trypanosomiasis American Amphotericin B Animal Model Area Artemisinins Ca(2+)-Transporting ATPase Calcium Cell physiology Cessation of life Chagas Disease Chemicals Class Clinical Condition Country Developed Countries Developing Countries Development Disease Drug Formulations Drug resistance Endoplasmic Reticulum Epidemic Exhibits Future HIV Health care facility Hepatic Homeostasis Human Human Cell Line Individual Infection Insecta Intramuscular Leishmania Leishmania donovani Leishmaniasis Life Locales Localized Skin Lesion Malaria Malnutrition Mesocricetus auratus Morbidity - disease rate Mucous Membrane Nose Numbers Oropharyngeal Pancreatitis Parasite resistance Parasites Patients Pharmaceutical Preparations Plasmodium Pneumonia Proteins Public Health Pump Rate Refugees Relapse Resistance Reticuloendothelial System Safety Southern Europe Stibogluconate Sodium Testing Therapeutic Therapeutic immunosuppression Toxic effect Transaminases Treatment Protocols Trypanosoma brucei brucei Trypanosoma cruzi Visceral Leishmaniasis Widespread Disease artemisinine base cellular targeting chemotherapeutic agent compliance behavior improved in vivo intravenous injection macrophage meglumine antimoniate mortality nephrotoxicity novel pathogen

项目摘要

DESCRIPTION (provided by applicant): Leishmania donovani (visceral leishmaniasis) and the trypanosomatid parasites T. cruzi (American Chagas disease) and T. brucei (African sleeping sickness) are significant causes of morbidity and mortality in tropical and subtropical areas worldwide. Current drug treatments for these pathogens have toxic side effects and are only partially effective due to increasing parasite drug resistance and poor patient compliance and tolerance. There is an urgent need for improved chemoprophylactic regimens for these human pathogens. Artemisinin and its derivatives are a safe and highly effective class of drugs whose introduction has had a major impact on the treatment of malaria. New artemisinin derivatives, such as artemisone, are even more effective and less toxic than the original artemisinins. Recently the intracellular target of artemisinin was identified as the Plasmodium endoplasmic reticulum calcium pump (SERCA). SERCA pumps are essential proteins that regulate internal calcium homeostasis, controlling an impressive and varied array of cellular functions. Evidence from our lab and others indicates that artemisinin and its derivatives, including artemisone, also inhibit Leishmania and the trypanosomatid parasites. These observations offer a unique opportunity to exploit a novel class of drugs with an excellent safety profile for Leishmania and trypanosomatid therapy. We have recently cloned the SERCA pump from L. donovani and propose to study the effects of artemisinin on LDSERCA and establish a basis for future studies on the T. brucei and T. cruzi SERCA pumps. The hypothesis to be tested is that artemisinin and artemisinin derivatives exhibit anti-leishmanial activity by targeting the Leishmania LDSERCA pump. Three specific aims are proposed. Specific aim 1. Determine the effects of artemisinins on Leishmania donovani promastigotes (insect and culture form) and amastigotes (host macrophage intracellular form) and human cell lines. Specific aim 2. Verify that the anti-leishmanial activity of artemisinins results from interaction with the L. donovani SERCA pump (LDSERCA). Specific aim 3. Determine the in vivo efficacy of artemisinins on Leishmania donovani infected Syrian Golden hamsters (Mesocricetus auratus). Specific aim 1 will establish that artemisinins have sufficient anti-leishmanial activity to merit consideration as a therapeutic option. Specific aim 2 will validate LDSERCA as the cellular target of artemisinin in L. donovani. Specific aim 3 will prove the efficacy of artemisinins in treating visceral leishmaniasis in an animal model. This will permit focused development of artemisinins as chemotherapeutic agents for visceral leishmaniasis and facilitate characterization of the effects of artemisinins on T. cruzi and T. brucei SERCAs.

描述（由申请人提供）：杜氏利什曼原虫（内脏利什曼病）和锥虫寄生虫克氏锥虫（美洲恰加斯病）和布氏锥虫（非洲昏睡病）是全世界热带和亚热带地区发病和死亡的重要原因。目前针对这些病原体的药物治疗具有毒副作用，并且由于寄生虫耐药性增加以及患者依从性和耐受性差而仅部分有效。迫切需要改进针对这些人类病原体的化学预防方案。青蒿素及其衍生物是一类安全高效的药物，其引入对疟疾的治疗产生了重大影响。新的青蒿素衍生物，例如青蒿素，比原始青蒿素更有效且毒性更小。最近，青蒿素的细胞内靶标被确定为疟原虫内质网钙泵（SERCA）。 SERCA 泵是调节内部钙稳态的重要蛋白质，控制着一系列令人印象深刻且多样化的细胞功能。我们实验室和其他实验室的证据表明，青蒿素及其衍生物（包括青蒿素）也能抑制利什曼原虫和锥虫寄生虫。这些观察结果为开发一类新型药物提供了独特的机会，该类药物对利什曼原虫和锥虫治疗具有出色的安全性。我们最近从 L. donovani 克隆了 SERCA 泵，并提出研究青蒿素对 LDSERCA 的影响，并为未来研究 T. brucei 和 T. cruzi SERCA 泵奠定基础。要测试的假设是青蒿素和青蒿素衍生物通过靶向利什曼原虫 LDSERCA 泵而表现出抗利什曼原虫活性。提出了三个具体目标。具体目标 1. 确定青蒿素对杜氏利什曼原虫前鞭毛体（昆虫和培养形式）和无鞭毛体（宿主巨噬细胞细胞内形式）和人类细胞系的影响。具体目标 2. 验证青蒿素的抗利什曼原虫活性是由与杜氏乳杆菌 SERCA 泵 (LDSERCA) 相互作用产生的。具体目标3.确定青蒿素对杜氏利什曼原虫感染的叙利亚金仓鼠（Mesocricetus auratus）的体内疗效。具体目标 1 将确定青蒿素具有足够的抗利什曼原虫活性，值得考虑作为一种治疗选择。具体目标 2 将验证 LDSERCA 作为青蒿素在杜氏乳杆菌中的细胞靶标。具体目标3将在动物模型中证明青蒿素治疗内脏利什曼病的功效。这将有助于集中开发青蒿素作为内脏利什曼病的化疗药物，并有助于表征青蒿素对克氏锥虫和布氏锥虫 SERCA 的作用。