Bosse Gabriel D, Urcino Cristoval, Watkins Maren, Flórez Salcedo Paula, Kozel Sabrina, Chase Kevin, Cabang April, Espino Samuel S, Safavi-Hemami Helena, Raghuraman Shrinivasan, Olivera Baldomero M, Peterson Randall T, Gajewiak Joanna
Department of Pharmacology and Toxicology, University of Utah, 201 Skaggs Hall 30 S 2000 E, Salt Lake City, Utah 84112, United States.
School of Biological Sciences, University of Utah, 257 S 1400 E, Salt Lake City, Utah 84112, United States.
J Nat Prod. 2021 Apr 23;84(4):1232-1243. doi: 10.1021/acs.jnatprod.0c01297. Epub 2021 Mar 25.
Natural products such as conotoxins have tremendous potential as tools for biomedical research and for the treatment of different human diseases. Conotoxins are peptides present in the venoms of predatory cone snails that have a rich diversity of pharmacological functions. One of the major bottlenecks in natural products research is the rapid identification and evaluation of bioactive molecules. To overcome this limitation, we designed a set of light-induced behavioral assays in zebrafish larvae to screen for bioactive conotoxins. We used this screening approach to test several unique conotoxins derived from different cone snail clades and discovered that a conorfamide from , CNF-Ep1, had the most dramatic alterations in the locomotor behavior of zebrafish larvae. Interestingly, CNF-Ep1 is also bioactive in several mouse assay systems when tested and . Our novel screening platform can thus accelerate the identification of bioactive marine natural products, and the first compound discovered using this assay has intriguing properties that may uncover novel neuronal circuitry.
诸如芋螺毒素之类的天然产物作为生物医学研究工具和治疗不同人类疾病的药物具有巨大潜力。芋螺毒素是存在于掠食性芋螺毒液中的肽，具有丰富多样的药理功能。天然产物研究的主要瓶颈之一是生物活性分子的快速鉴定和评估。为克服这一限制，我们设计了一组针对斑马鱼幼体的光诱导行为分析方法来筛选生物活性芋螺毒素。我们使用这种筛选方法测试了几种源自不同芋螺分支的独特芋螺毒素，发现来自芋螺Conus episcopatus的一种芋螺酰胺CNF-Ep1对斑马鱼幼体的运动行为有最显著的改变。有趣的是，在进行测试时，CNF-Ep1在几种小鼠分析系统中也具有生物活性。因此，我们的新型筛选平台可以加速生物活性海洋天然产物的鉴定，并且使用该分析方法发现的首个化合物具有可能揭示新神经回路的有趣特性。
