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Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease

开发一种新的海洋天然产品来治疗隐孢子虫病（一种艾滋病定义的疾病）

基本信息

批准号：
10076207
负责人：
ROBERTA M O'CONNOR
金额：
$ 47.41万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10076207
关键词：
Acquired Immunodeficiency Syndrome Acute Antiparasitic Agents Area Bacteria Biological Availability Cells Cessation of life Characteristics Chronic Clinical Complex Consumption Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Developed Countries Developing Countries Development Diarrhea Disease Dose Drug Kinetics Future Growth Immune Immunocompromised Host Immunosuppression In Vitro Individual Infant Infection Institutes Intestines Invertebrates Investigation Length Life Cycle Stages Luciferases Medical Mining Modeling Mus Natural Products Neonatal Oocysts Organoids Parasites Patients Pharmaceutical Preparations Pharmacodynamics Process Production Property Protocols documentation Regimen Reporting Ruminants Species Specificity Specificity Sporozoites Staphylococcus hominis Structure Symptoms Testing Therapeutic Time Toxic effect Treatment Efficacy Wood material Work asexual design diarrheal disease effective therapy gastrointestinal human disease immunosuppressed in vivo innovation lead candidate marine natural product mouse model neglect nitazoxanide optimal treatments pathogen symbiont therapeutic candidate treatment optimization treatment strategy waterborne waterborne outbreak

项目摘要

ABSTRACT There are no effective therapies to treat Cryptosporidium, a waterborne parasite that is now recognized as significant cause of diarrheal disease worldwide and an important AIDS defining pathogen. In the process of mining compounds produced by marine symbiotic bacteria for anti-parasitic activity, we identified a compound, tartrolon E (trtE) that potently inhibits in vitro growth of Cryptosporidium parvum, as well as several other apicomplexan parasites, without toxicity to their respective host cells. We further established that trtE is highly effective at reducing Cryptosporidium infection in neonatal mice. In fact, trtE is 10-fold more effective in vitro and 2-fold more effective in vivo against Cryptosporidium than the most effective compounds reported to date, and the only compound to hold the promise of a broad spectrum anti-apicomplexan therapeutic. These observations strongly encourage further exploration of the clinical potential of trtE for the treatment of cryptosporidiosis. In the studies proposed here, we will test the hypothesis that trtE possesses the activity necessary to be lead candidate therapeutic for the treatment of cryptosporidiosis by completion of the following aims: Aim 1: To evaluate species specificity and life cycle stage specificity of trtE against Cryptosporidium. TrtE will be tested against C. parvum field isolates and C. hominis and the activity of trtE against oocysts, sporozoites, asexual and sexual stages will be determined. Aim 2: To optimize trtE dosing regimens. Pharmacodynamics (A), pharmacokinetics (B) and bioavailability (C) studies will be conducted to design optimal treatment strategies. Aim 3: To evaluate the efficacy of trtE against Cryptosporidium infection in the setting of severe immunosuppression and in a ruminant model of cryptosporidiosis. A. We will test trtE’s ability to inhibit and eliminate Cryptosporidium infection in NOD-SCID gamma mice. B. Because mice do not manifest the symptoms of human disease, we will test the trtE’s ability to inhibit infection and diarrheal illness in neonatal lambs. Aim 4: To optimize production of trtE from Teredinibacter turnerae T7901: Like many natural products, trtE has a complex structure that renders synthesis challenging and prohibitively expensive. The Natural Products Discovery Institute (NPDI), experts in the field of natural product production, will be producing trtE for these studies using established protocols. During that process, NPDI will apply their expertise in this area to increase production efficiency. These studies will provide data essential to establish trtE as a lead candidate for an anti-Cryptosporidium therapeutic. Moreover, because this compound is highly active against multiple parasites, these investigations will underpin future studies evaluating this compound as a broad spectrum therapeutic for diseases caused by apicomplexan parasites, but most critically for cryptosporidiosis, a neglected disease of world-wide significance for which there are no good therapeutic options.

摘要