韩国首尔大学医学院Sangsu Bae小组近日取得一项新成果。经过不懈努力，他们研究出AI生成的MLH1小分子结合剂提升引导编辑效率。2025年8月5日，国际知名学术期刊《细胞》发表了这一成果。

该课题组设计了一种全新的MLH1小结合剂（MLH1- sb），它结合在MLH1和PMS2的二聚体界面上，主题为RFdiffthemion和AlphaFold 3。MLH1-SB的紧凑尺寸使其能够通过2A系统集成到现有的PE架构中，从而创建一个PE-SB平台。PE7-SB2系统显著提高了PE效率，在HeLa细胞中比PEmax提高18.8倍，比PE7提高2.5倍，在小鼠中比PE7提高3.4倍。这项研究突出了生成式人工智能在推进基因组编辑技术方面的潜力。

据悉，引体编辑（PE）系统由一个以逆转录酶为主题的Cas9缺口酶组成，该酶在PE引导RNA的引导下将精确的编辑引入目标基因组区域。然而，PE效率受到错配修复的限制。为了克服这一限制，研究人员对显性阴性MLH1 （MLH1dn）的瞬时表达进行了主题研究，以抑制错配修复的关键成分。

附：英文原文

Title: AI-generated MLH1 small binder improves prime editing efficiency

Author: Ju-Chan Park, Heesoo Uhm, Yong-Woo Kim, Ye Eun Oh, Jang Hyeon Lee, Jiyun Yang, Kyoungmi Kim, Sangsu Bae

Issue&Volume: 2025-08-05

Abstract: The prime editing (PE) system consists of a Cas9 nickase fused to a reverse transcriptase, which introduces precise edits into the target genomic region guided by a PE guide RNA. However, PE efficiency is limited by mismatch repair. To overcome this limitation, transient expression of a dominant-negative MLH1 (MLH1dn) has been used to inhibit key components of mismatch repair. Here, we designed a de novo MLH1 small binder (MLH1-SB) that binds to the dimeric interface of MLH1 and PMS2 using RFdiffusion and AlphaFold 3. The compact size of MLH1-SB enabled its integration into existing PE architectures via 2A systems, creating a PE-SB platform. The PE7-SB2 system significantly improved PE efficiency, achieving an 18.8-fold increase over PEmax and a 2.5-fold increase over PE7 in HeLa cells, as well as a 3.4-fold increase over PE7 in mice. This study highlights the potential of generative AI in advancing genome editing technology.

DOI: 10.1016/j.cell.2025.07.010

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00799-8