Cell重磅：AI从头设计生成小型结合蛋白，大幅提高先导编辑效率

Core Viewpoint - The article discusses advancements in prime editing (PE) technology, particularly focusing on the development of MLH1 small binders (MLH1-SB) using AI tools to enhance editing efficiency in genome editing applications [2][4]. Group 1: Prime Editing Technology - Prime editing is a novel genome editing technique that allows for precise modifications, including base substitutions and small insertions or deletions [2]. - The efficiency of prime editing is often limited by the mismatch repair (MMR) pathway, which can hinder the integration of desired edits at target sites [6][7]. Group 2: AI-Driven Innovations - The research utilized the AI protein design tool RFdiffusion to create MLH1 small binders that inhibit MMR activity, thereby improving prime editing efficiency [3][9]. - AlphaFold3 was employed to efficiently screen the designed proteins, leading to the identification of an optimal MLH1-SB composed of only 82 amino acids, which integrates well with existing PE architectures [10][11]. Group 3: Efficiency Improvements - The newly developed PE-SB platforms, such as PEmax-SB, PE6-SB, and PE7-SB, demonstrated significant improvements in editing efficiency, with PE7-SB2 showing an increase of approximately 18.8 times compared to PEmax and 2.5 times compared to PE7 in human cells [11]. - In vivo studies indicated that PE7-SB2's efficiency was about 3.4 times greater than that of PE7 in mouse models [11]. Group 4: Implications for Gene Therapy - The compact size of the MLH1-SB allows for easier integration and delivery in gene therapy applications, which is crucial for effective in vivo gene editing [11]. - The advancements in AI-driven protein design are expected to facilitate the development of efficient gene editing therapies, potentially transforming the landscape of genetic medicine [15].