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

这个小企业创新研究（SBIR）第一阶段项目创建了一个药物筛选平台，用于发现新的抗寄生虫药物。对当前药物治疗的耐药性正在上升。目前正在开发的新型抗寄生虫药物主要针对神经传递靶点，但最近出现了一个新的靶点，即daf-12基因。Knudra利用线虫生物工程方面的核心专业知识，将寄生虫基因植入秀丽隐杆线虫。通过使用生物传感器背景找到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器，在检测到抗寄生虫活性时变为红色。当已知的DAF-12激动剂和拮抗剂对寄生虫基因产生预期的活性时，证明了I期可行性。该平台可用于筛选化合物文库，以找到候选的驱虫药。这个项目如果成功，其更广泛的影响/商业潜力将是创建一个筛选平台，用于寻找抗寄生虫药，以帮助防治重要疾病，如象皮病、河盲症、旋毛虫病、肠虫病（蛲虫）以及牲畜和作物中的寄生虫感染。目前，市场上有20多种治疗牲畜和人类寄生虫感染的药物，但其中一些是有毒的，并带有黑框警告。随着更安全、更有效的新型抗寄生虫药的开发，全世界的粮食和卫生安全将得到加强。此外，该技术将有助于对寄生虫生命周期中感染状态形成的生物学有更清晰的认识。

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.