Great advances have been made over the last four decades in therapeutic and diagnostic applications of antibodies. The activity maturation of antibody candidates, however, remains a significant challenge. To address this problem, we present a method that enables the systematic enhancement of the activity of a single-domain antibody through the post-translational installation of non-canonical side chains by chemical mutagenesis. We illustrate this approach by performing a structure-activity relationship study beyond the 20 naturally occurring amino acids on a single-domain antibody designed in silico to inhibit the aggregation of the amyloid-β peptide, a process closely linked to Alzheimer's disease. We found that this approach can improve, by five orders of magnitude, the anti-aggregation activity of the starting single-domain antibody, without affecting its stability. These results show that the expansion of the chemical space available to antibodies through chemical mutagenesis can be exploited for the systematic enhancement of the activity of these molecules.

在过去的四年里，抗体的治疗和诊断应用取得了巨大进步。然而，候选抗体的活性成熟仍然是一个重大挑战。为了解决这个问题，我们提出了一种方法，通过化学诱变非规范侧链的翻译后安装，能够系统地增强单域抗体的活性。我们通过对计算机设计的单域抗体进行超过 20 个天然氨基酸的构效关系研究来说明这种方法抑制淀粉样蛋白-β 肽的聚集，这一过程与阿尔茨海默病密切相关。我们发现这种方法可以将起始单域抗体的抗聚集活性提高五个数量级，而不会影响其稳定性。这些结果表明，通过化学诱变扩大抗体可用的化学空间可用于系统地增强这些分子的活性。