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Angew Chem Int Ed Engl. 2021 Oct 11;60(42):22640-22645. doi: 10.1002/anie.202103043. Epub 2021 Sep 6.
Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding the chemical diversity of macrocycles beyond what is accessible in nature. Such libraries have incorporated non-natural amino acids at the expense of natural amino acids by reassigning their codons. Here we report an alternative approach to expanded amino-acid diversity that preserves all 19 natural amino acids (no methionine) and adds 6 non-natural amino acids, resulting in the highest sequence complexity reported to date. We have applied mRNA display to this 25-letter library to select functional macrocycles that bind human STING, a protein involved in immunoregulation. The resulting STING-binding peptides include a 9-mer macrocycle with a dissociation constant (K ) of 3.4 nM, which blocks binding of cGAMP to STING and induces STING dimerization. This approach is generalizable to expanding the amino-acid alphabet in a library beyond 25 building blocks.
近年来，mRNA 展示技术的进步使得能够选择包含非天然氨基酸的肽，从而将大环的化学多样性扩展到自然界中无法获得的范围之外。这些文库通过重新分配它们的密码子来牺牲天然氨基酸以纳入非天然氨基酸。在这里，我们报告了一种扩展氨基酸多样性的替代方法，该方法保留了所有 19 种天然氨基酸（不含蛋氨酸）并添加了 6 种非天然氨基酸，这是迄今为止报道的最高序列复杂性。我们已经将 mRNA 展示技术应用于这个 25 个字母的文库中，以选择能够结合人类 STING 的功能性大环，STING 是一种参与免疫调节的蛋白质。所得的 STING 结合肽包括一个解离常数 (K ) 为 3.4 nM 的 9 肽大环，它阻断 cGAMP 与 STING 的结合并诱导 STING 二聚化。这种方法可推广到将文库中的氨基酸字母扩展到 25 个构建块之外。
