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).

止痛药作为日常用药普遍存在。天然肽类止痛药存在诸多药理劣势，而如吗啡这类小分子止痛药则具有高度成瘾性。本研究提出了一种基于骨架环化反应以开发肽类类似物止痛药的一般方法。通过对线性肽Tyr-Arg-Phe-Sar（TAPS）进行骨架环化改造，我们成功将其转化为具有优化药理特性的活性骨架环状肽。我们设计并合成了一个具有构象多样性的聚焦骨架环状TAPS文库，其中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上氮原子上的烷基链长度。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了评估。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，并具有成为具有μ阿片受体完全激动剂功能的周围性止痛药的潜力。为大量制备TAPS c(2-6)，我们优化了树脂上还原烷基化步骤的条件，以提高其固相肽合成（SPPS）的效率。核磁共振技术被用于确定肽类先导化合物TAPS c(2-6)的溶液构象。