Large macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable cross‐β conformations, and found that peptoid substitutions within the β‐turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing β‐strands led to “chameleonic” species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity.

中文翻译：

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MW 1000以上大循环中的类药物特性：骨架刚度与侧链亲脂性

大的大环肽可以实现令人惊讶的高膜渗透性，尽管控制该化学空间中渗透性的特性才刚刚开始受到关注。我们生成了两个具有稳定的交叉β构象的环状十肽文库，发现大环β内的类肽取代保留了母体支架的刚性，而相反的β链上的类肽取代导致了“衣原体”物种在非极性介质中是刚性的，但在水中具有高度柔性。刚性化合物和Chameleonic化合物均在较宽的亲脂性范围内显示出高渗透性，其峰磁导率差异取决于支架的刚性。