Life history-guided drug discovery from venomous marine snails

总结 芋螺总科中的有毒海洋蜗牛通过注射一种复合物来捕获猎物 核糖体合成的肽的混合物，其经历广泛的翻译后修饰。 这些锥肽靶向猎物神经、内分泌和神经系统中的受体和离子通道， 感觉系统具有显著的效力和特异性。由于其多样性和目标 选择性，锥肽已成为离子通道研究的宝贵工具， 治疗学使用锥螺毒液作为药物发现来源的基本原理是， 在锥螺的猎物中表达的许多分子靶标的同源物也在人类中发现 它们与多种生理紊乱有关，包括炎症，癫痫， 神经性疼痛和糖尿病。我的团队最近的几项发现表明， 大约700种锥形蜗牛中的每一种都产生一套独特的锥形肽， 一组特定的受体。因此，这项资助的核心假设是， 通过测序和鉴定许多毒液的成分， 物种从不同谱系的锥螺，包括那些诱导不同的生理 它们的猎物。这是一种高度创新的方法，因为它充分利用了 在这些动物中进化出的捕捉猎物的独特策略：诱导快速麻痹的物种 在它们的猎物中很可能会表达针对神经肌肉接头和疼痛回路的毒素 而那些引起活动减退和镇静的细胞更有可能进化出毒素， 针对感觉和内分泌系统。我们的初步研究已经确定了几个 糖尿病是一种公认的全球性疾病， 流行病和疼痛，这是目前阿片类药物流行病的主要原因。这项建议将使我们能够 有效地扩展这些有前途的初步努力。该项目的具体目标是（目标1）， 进行大规模的，进化引导的收集和下一代测序工作， 毒液从所有~50个主要谱系的锥形蜗牛，（目的2）开发一个创新的计算 流水线，Taxpipeline毒液模块，分析这些大型测序数据集，以及（目标3） 使用分层的、数据驱动的选择过程， 新的毒素。我们还将寻求鉴定和表征芋螺肽 生物合成途径这样做将改善用于生产生物制品的合成和重组手段。 用于功能研究的多肽。预期成果是重要的。核心提供 药物发现的计算管道，这将导致许多新的类别的识别， 芋螺肽及其生物合成酶，将推动科学发现和药物 未来几十年的发展。

SUMMARY Venomous marine snails in the superfamily Conoidea capture their prey by injecting a complex mixture of ribosomally-synthesized peptides that undergo extensive post-translational modification. These conopeptides target receptors and ion channels in the prey's nervous, endocrine and sensory system with remarkable potency and specificity. Owing to their diversity and target selectivity, conopeptides have become invaluable tools for ion channel research and as therapeutics. The rationale of using cone snail venoms as a source for drug discovery is that homologs of many molecular targets expressed in the prey of cone snails are also found in humans where they are implicated in diverse physiological disorders, including inflammation, epilepsy, neuropathic pain and diabetes. Several recent discoveries made in my group now demonstrate that each of the ~700 cone snail species produces a distinct set of conopeptides that are finely tuned for a specific set of receptors in its prey. Thus, the central hypothesis of this grant is that drug discovery can be maximized by sequencing and characterizing the venom composition of many species from diverse lineages of cone snails, including those that induce diverse physiological endpoints in their prey. This is a highly innovative approach because it takes full advantage of the unique strategies that evolved in these animals for prey capture: species that induce rapid paralysis in their prey are likely to express toxins that target the neuromuscular junction and pain circuits whereas those that induce hypoactivity and sedation are more likely to have evolved toxins that target the sensory and endocrine system. Our preliminary research has already identified several unique drug leads for the treatment of diabetes, a disease that has been recognized as a global epidemic, and pain, a leading cause for the current opioid epidemic. This proposal will enable us to efficiently scale these promising initial efforts. The specific aims of this project are (Aim 1) to undertake a large-scale, evolution-guided collection and next-generation sequencing effort of venoms from all ~50 major lineages of cone snails, (Aim 2) to develop an innovative computational pipeline, the Taxonomer Venoms Module, to analyze these large sequencing datasets, and (Aim 3) to use a tiered, data-driven selection process to pharmacologically characterize the most promising novel toxins from these large datasets. We will also seek to identify and characterize conopeptide biosynthetic pathways. Doing so will improve synthetic and recombinant means for production of conopeptides for functional studies. The expected outcomes are significant. We will provide a computational pipeline for drug discovery that will lead to the identification of many novel classes of conopeptides and their biosynthetic enzymes that will fuel scientific discovery and drug development activities for decades to come.