Data_Sheet_1_Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.PDF

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).

止痛药作为一种常用的药物，广泛应用于临床。天然肽类止痛药虽具有多种药理优势，但小分子止痛药如吗啡则具有较高的成瘾性。本研究提出一种通用的方法，旨在通过骨架环化技术来开发一种肽模拟类止痛药。通过对线性肽Tyr-Arg-Phe-Sar（TAPS）进行骨架环化处理，成功转化为具有改进药理特性的活性骨架环状肽。本研究设计并合成了一种具有构象多样性的聚焦骨架环状TAPS文库，文库成员的通用名称为TAPS c(n-m)，其中n和m分别代表Gly和Arg氨基上烷基链的长度。我们采用联合筛选方法对TAPS c(n-m)文库的药理特性和活性进行评估。我们重点关注了一种体内活性化合物，TAPS c(2-6)，该化合物具有代谢稳定性，并且作为一种全μ型阿片受体激动剂，具有成为外周止痛药的潜力。为了大量制备TAPS c(2-6)，我们优化了树脂上还原烷基化步骤的条件，以提高其SPPS（固相肽合成）的效率。核磁共振技术被用于确定肽先导化合物TAPS c(2-6)的溶液构象。