A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size and polarity of these compounds prevents them from crossing the cell membrane to reach target sites in the cell cytosol. As such, these compounds do not conform to standard measures of drug-likeness and exist in beyond the rule-of-five space. In this work, we investigate whether prodrug moieties that mask hydrogen bond donors can be applied in the beyond rule-of-five domain to improve the permeation of macrocyclic compounds. Using a cyclic peptide model, we show that masking hydrogen bond donors in the natural polar amino acid residues (His, Ser, Gln, Asn, Glu, Asp, Lys, and Arg) imparts membrane permeability to the otherwise impermeable parent molecules, even though the addition of the masking group increases the overall compound molecular weight and the number of hydrogen bond acceptors. We demonstrate this strategy in PAMPA and Caco2 membrane permeability assays and show that masking with groups that reduce the number of hydrogen-bond donors at the cost of additional mass and hydrogen bond acceptors, a donor–acceptor swap, is effective.

中文翻译：

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通过使用前药掩盖氢键供体，改善在五规则之外的膜渗透性。

肽和大环化合物可以有效地调节多种药物靶标。不幸的是，这些化合物的大小和极性阻止它们穿过细胞膜到达细胞溶质中的靶位。因此，这些化合物不符合药物相似性的标准量度，并且存在于五规则范围之外。在这项工作中，我们调查掩盖氢键供体的前药部分是否可以应用于五规则以外的领域，以改善大环化合物的渗透性。使用环状肽模型，我们证明掩盖了天然极性氨基酸残基（His，Ser，Gln，Asn，Glu，Asp，Lys和Arg）中的氢键供体会赋予原本不可渗透的母体分子膜渗透性，即使添加掩蔽基团也会增加化合物的整体分子量和氢键受体的数量。我们在PAMPA和Caco2膜通透性测定法中证明了该策略，并表明以减少额外的质量和氢键受体，供体-受体交换为代价的减少氢键供体数量的基团进行掩蔽是有效的。