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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
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由deoxyoligonucleotides编码的面向多样性的合成.

Liam Hudson1,2, Jeremy W Mason1,2, Matthias V Westphal1,2

  • 1Chemical Biology and Therapeutics Science Program, Broad Institute, 415 Main Street, Cambridge, MA, 02142, USA.

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|August 15, 2023
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此摘要是机器生成的。

面向多样性的合成 (DOS) 能够创造新的分子. 这项研究引入了使用DOS的大型DNA编码库 (DEL),以增强结构多样性,加速药物发现.

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科学领域:

  • 药用化学 医学化学
  • 化学生物学 化学生物学
  • 药物发现 药物发现 药物发现

背景情况:

  • 面向多样性的合成 (DOS) 产生具有独特结构特征的分子.
  • DNA编码图书馆 (DEL) 对于选蛋白质结合剂是有效的,但通常受到DNA构造灵敏度的限制.
  • 目前的DEL合成可以在结构多样性上受到限制,通常依赖于附属物变异.

研究的目的:

  • 使用DOS原则设计和合成一个大型,结构多样化的DNA编码库.
  • 通过结合不同的骨架架构和退出向量来克服传统DEL合成的局限性.
  • 为了证明这种新型DEL对查蛋白标的有用性,并加速早期药物发现.

主要方法:

  • 利用以多样性为导向的合成 (DOS) 策略来构建复杂的分子支架.
  • 开发了一个拥有370万个成员的DNA编码库 (DEL),具有多样化的骨架架构和退出向量.
  • 对三个不同的蛋白质标进行了选实验,以验证图书馆的实用性.

主要成果:

  • 成功地产生了一个大型的DEL (3.7百万成员),其结构多样性远远超过附属物变化.
  • 证明了DOS衍生的DEL在识别蛋白质结合物的有效性.
  • 获得了三种不同的蛋白质标的选结果,展示了该库的适用性.

结论:

  • 开发的基于DOS的DEL显著扩大了通过DEL技术可访问的结构多样性.
  • 这种方法克服了与传统DEL合成中的敏感DNA结构相关的局限性.
  • 该DEL将向科学界提供,以促进早期药物发现和识别新生物机制.