近日，加拿大麦吉尔大学Hanadi F. Sleiman团队报道了利用DNA正交条形码解锁适体的化学多样性。2026年5月6日，《自然-化学》杂志发表了这一成果。

适配体是抗体的多功能替代品，因其体积更小、更易合成且免疫原性更低。然而，抗体由20种化学性质多样的氨基酸组成，已是成熟的治疗药物，而适配体仅由4种相似的核碱基构成，这限制了它们的治疗潜力。适配体的化学修饰受到限制，必须保持与酶促筛选的兼容性。

研究组引入类适配体编码寡聚物（alenomer），这是一种经过高度化学修饰的适配体，通过从靶标结合寡聚物分支出来并与之对应的DNA编码进行读取和测序。研究组使用自动化DNA合成仪及分选-合并方法，构建了约30万成员数的DNA编码文库，并通过下一代测序筛选其中与蛋白质结合的序列。与适配体不同，alenomer不受保守的酶兼容性修饰要求的限制。因此，它们能够探索几乎无限的化学空间，从而发现高度稳定、高亲和力的蛋白质结合类适配体分子，同时提供关于其与靶标分子相互作用的结构性见解。

附：英文原文

Title: Unlocking chemical diversity in aptamers with DNA orthogonal barcodes

Author: Saliba, Daniel, Osman, Eiman A., Elmanzalawy, Abdelrahman, Saab, Christopher, Bui, Son, Hirka, Serhii, Anderson, Shaun, Toader, Violeta, Dore, Michael D., Rizzuto, Felix J., de Rochambeau, Donatien, McKeague, Maureen, Sleiman, Hanadi F.

Issue&Volume: 2026-05-06

Abstract: Aptamers are a versatile alternative to antibodies as they are smaller, easier to synthesize and less immunogenic. However, while antibodies are composed of 20 chemically diverse amino acids and are established therapeutics, aptamers are composed of only 4 similar nucleobases, thereby limiting their therapeutic potential. Aptamer chemical modifications are restricted to maintain compatibility with enzymatic selection. Here we introduce aptamer-like encoded oligomers (alenomers), highly chemically modified aptamers that are read and sequenced using a DNA code branching from and corresponding to the target-binding oligomer. We build ~300,000-member DNA-encoded libraries using an automated DNA synthesizer and split-and-pool methods, and screen them for protein binding via next-generation sequencing. In contrast to aptamers, alenomers are not restricted by the need for conservative enzyme-compatible modifications. They can thus explore an almost limitless chemical space, enabling the discovery of highly stable, high-affinity protein-binding aptamers, while offering structural insights into their interactions with target molecules.

DOI: 10.1038/s41557-026-02099-5

Source: https://www.nature.com/articles/s41557-026-02099-5