High-Purity Peptide Libraries without Chromatographic Separation

描述（由申请人提供）：肽和蛋白质产品的市场每年为300亿美元，并且还在继续增长。自动化固相肽合成（SPPS）是现代医学研究的支柱，已在微摩尔到公吨的工业规模上得到应用。肽类药物如艾塞那肽（一种GLP-1类似物，是许多2型糖尿病患者的救命药）和治疗艾滋病的Fuzeon，如果不是用于SPPS，就不会存在。不完整合成步骤导致的错误序列限制了SPPS的效率和吞吐量，通常需要费力和昂贵的分离。我们的技术通过在后台（在标准冷凝步骤之间）进行化学校对，而无需修改现有方法，为该问题提供了一种新颖的解决方案。在几分钟内，任何未反应的部位都被惰性的碳氟化合物残留物覆盖。因此，错误序列被简化为不可溶的结构，可以在最后以轻松的方式删除。我们的初步研究一致地提供了分离的全长肽，特别是在以前需要重复HPLC纯化的情况下。我们的目标是将这项技术扩展到无差错合成肽库的合成。达到高纯度将建立

DESCRIPTION (provided by applicant): The market for peptide and protein products is $30 billion annually and continues to grow. Automated solid phase peptide synthesis (SPPS) is a mainstay of modern medicinal research, and has been used on micromole up to metric ton industrial scale. Peptide drugs such as Exenatide, a GLP-1 analogue and a life-saver to many type-2 diabetes patients, and Fuzeon for HIV-AIDS would not exist but for SPPS. Error sequences resulting from incomplete synthetic steps limit the efficiency and throughput of SPPS, often requiring laborious and costly separations. Our technology offers a novel solution to the problem via a chemical proofreading that takes place in the background (between standard condensation steps) with no modification to established methods. Within minutes, any unreacted sites are capped with inert fluorocarbon residues. The error sequences are thus reduced into insoluble constructs that can be removed in a facile manner at the end. Our preliminary studies have consistently afforded isolated full- length peptides, and especially in cases previously subject to repeated HPLC purification. We aim to expand this technology to the synthesis of error-free synthesis of peptide libraries. Achieving high purities would establish a new empowering standard in peptide research. Our research program at Tufts has experience in the study of G- Protein coupled receptors (GPCRs) and has produced notable innovations in the design and synthesis of novel peptide ligands. We therefore propose the synthesis of libraries of GLP-1 analogs, embodying novel and unnatural amino-acid motifs. Taken together, these studies will result in efficient library synthesis of peptides with purities exceeding 70% without the need for purification by chromatography and may result in a therapeutically relevant compound for diabetes at the end of the project period.