The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead–based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

中文翻译：

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通过双接头固相合成获得高纯度 DNA 编码化学文库


第一批使用 DNA 编码化学库 (DEL) 筛选发现的药物已进入后期临床开发。然而，DEL 技术作为一个整体仍然存在化学纯度较差的问题，导致性能欠佳。在这项工作中，我们报告了一种通过磁珠合成后自净化释放 DEL 来克服这个问题的技术。每个组装的文库成员的第一个和最后一个构件都通过可通过相互正交的化学作用裂解的系链与珠子连接。第一个和最后一个系链的顺序裂解以及中间的洗涤确保了最终的文库仅包含完全完整的化合物。通过这种方法获得的出色纯度能够实现化学显示和编码的直接关联，允许扩大化学反应范围，并促进使用更多多样性元素，同时大大提高选择中的信噪比。