SBIR Phase I: A Platform for Anthelmintic Drug Discovery using DAF-12 as a Novel Target

这个小型企业创新研究(SBIR)第一阶段项目为发现新的抗寄生虫药物创建了一个药物筛选平台。对当前药物治疗的耐药性正在上升。正在开发的新的抗寄生虫药物主要集中在神经传递靶点上，但最近出现了一个新的靶点，daf-12基因。Knudra利用线虫生物工程的核心专业知识将寄生虫基因注入线虫蛔虫。通过使用生物传感器背景，可以发现针对寄生虫基因的候选药物，生物传感器背景使用荧光基因表达报告，在检测到抗寄生虫活性时，荧光基因表达报告变为红色。当DAF-12的已知激动剂和拮抗剂在寄生虫基因上引起预期的活性时，第一阶段的可行性被证明。该平台随后可用于筛选化合物文库，以寻找驱虫药的候选者。如果该项目成功，该项目的更广泛影响/商业潜力将是创建一个寻找抗寄生虫药物的筛选平台，以帮助抗击重要疾病，如象皮病、河盲症、旋毛虫病、肠道线虫病(蛔虫)以及牲畜和农作物中的寄生虫感染。目前，市场上有20多种药物可以治疗牲畜和人类的寄生虫感染，但其中一些是有毒的，并带有黑匣子警告。随着更安全和更有效的新抗寄生虫药物的开发，全世界的粮食和卫生安全将得到加强。此外，这项技术将有助于清楚地了解寄生虫生命周期中感染状态形成的生物学。

This Small Business Innovation Research (SBIR) Phase I project creates a drug-screening platform for discovery of new antiparasitic drugs. Resistance to current drug treatments is on the rise. New antiparasitic drugs under development are mostly focused on neurotransmission targets, yet a new target has recently emerged, the daf-12 gene. Knudra uses a core expertise in nematode bioengineering to insert parasite genes into the C. elegans roundworm. Drug candidates are found against the parasite gene by the use of biosensor backgrounds, which use fluorescent gene-expression reporters that turn red upon detection of antiparasitic activity. Phase I feasibility is demonstrated when known agonist and antagonist of DAF-12 elicit expected activity on the parasite gene. The platform may then be used to screen compound libraries to find candidates for anthelmintic use.The broader impact/commercial potential of this project, if successful, will be the creation of a screening platform for finding antiparasitics to help in the battle against important diseases such as elephantiasis, river blindness, trichinosis, Enterobiasis (pinworm), and parasitic infections in livestock and crops. Parasitic infection in livestock and humans currently are treated with more than 20 drugs on the market, but some are toxic and carry black box warnings. Food and health security throughout the world would be enhanced with the development of new antiparasites that are safer and more effective. In addition, the technology will help to bring clarity of understanding to the biology of infective-state formation in parasite lifecycle.