Abiotic peptides as carriers of information for the encoding of small-molecule library synthesis

• 成果类型: Article
• 署名作者: Rossler, Simon L.; Grob, Nathalie M.; Buchwald, Stephen L.; Pentelute, Bradley L.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13331
• DOI: 10.1126/science.adf1354
• 发表日期: 2023-03-03
• 页码: 939-945
• 关键词: dna; DESIGN; DISCOVERY; proteins; SYSTEM

摘要

Encoding small-molecule information in DNA has been leveraged to accelerate the discovery of ligands for therapeutic targets such as proteins. However, oligonucleotide-based encoding is hampered by inherent limitations of information stability and density. In this study, we establish abiotic peptides for next-generation information storage and apply them for the encoding of diverse small-molecule synthesis. The chemical stability of the peptide-based tag allows the use of palladium-mediated reactions to efficiently synthesize peptide-encoded libraries (PELs) with broad chemical diversity and high purity. We demonstrate the successful de novo discovery of small-molecule protein ligands from PELs by affinity selection against carbonic anhydrase IX and the oncogenic protein targets BRD4(1) and MDM2. Collectively, this work establishes abiotic peptides as carriers of information for the encoding of small-molecule synthesis, leveraged herein for the discovery of protein ligands.