Al Mazid Mohammad Faysal, Shkel Olha, Ryu Eunteg, Kim Jiwon, Shin Kyung Ho, Kim Yun Kyung, Lim Hyun Suk, Lee Jun-Seok
Division of Bio-Medical Science and Technology, Korea Institute of Science and Technology (KIST) & Department of Biological Chemistry, KIST School UST, Seoul 02792, South Korea.
Department of Pharmacology, College of Medicine, Korea University, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, South Korea.
ACS Chem Biol. 2024 Dec 20;19(12):2462-2468. doi: 10.1021/acschembio.4c00536. Epub 2024 Dec 4.
Target protein degradation (TPD) is a promising strategy for catalytic downregulation of target proteins through various cellular proteolytic pathways. Despite numerous reports on novel TPD mechanisms, the discovery of target-specific ligands remains a major challenge. Unlike small-molecule ligands, aptamers offer significant advantages, owing to their SELEX-based systematic screening method. To fully utilize aptamers for TPD, we designed an aptamer and N-degron ensemble system (AptaGron) that circumvents the need for synthetic conjugations between aptamers and proteolysis-recruiting units. In our AptaGron system, a peptide nucleic acid containing an N-degron peptide and a sequence complementary to the aptamer was designed. Using this system, we successfully degraded three target proteins, tau, nucleolin, and eukaryotic initiation factor 4E (eIF4E), which lack specific small-molecule ligands. Our results highlight the potential of the AptaGron approach as a robust platform for targeted protein degradation.
靶向蛋白质降解（TPD）是一种通过各种细胞蛋白水解途径对靶蛋白进行催化下调的有前景的策略。尽管有许多关于新型TPD机制的报道，但发现靶标特异性配体仍然是一个重大挑战。与小分子配体不同，适体具有显著优势，这得益于其基于指数富集的配体系统进化技术（SELEX）的系统筛选方法。为了充分利用适体进行TPD，我们设计了一种适体和N-降解子整合系统（AptaGron），该系统无需在适体和蛋白水解招募单元之间进行合成偶联。在我们的AptaGron系统中，设计了一种包含N-降解子肽和与适体互补序列的肽核酸。使用该系统，我们成功降解了三种缺乏特异性小分子配体的靶蛋白，即tau蛋白、核仁素和真核翻译起始因子4E（eIF4E）。我们的结果突出了AptaGron方法作为一种强大的靶向蛋白质降解平台的潜力。
