An enzyme cascade enables production of therapeutic oligonucleotides in a single operation

• 成果类型: Article
• 署名作者: Moody, E. R.; Obexer, R.; Nickl, F.; Spiess, R.; Lovelock, S. L.
• 署名单位: University of Manchester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13308
• DOI: 10.1126/science.add5892
• 发表日期: 2023-06-16
• 页码: 1150-1154
• 关键词: diastereomeric phosphorothioate analogs; dna-polymerase; liquid-phase; mechanism; EVOLUTION; platform; coli; rna

摘要

Therapeutic oligonucleotides have emerged as a powerful drug modality with the potential to treat a wide range of diseases; however, the rising number of therapies poses a manufacturing challenge. Existing synthetic methods use stepwise extension of sequences immobilized on solid supports and are limited by their scalability and sustainability. We report a biocatalytic approach to efficiently produce oligonucleotides in a single operation where polymerases and endonucleases work in synergy to amplify complementary sequences embedded within catalytic self-priming templates. This approach uses unprotected building blocks and aqueous conditions. We demonstrate the versatility of this methodology through the synthesis of clinically relevant oligonucleotide sequences containing diverse modifications.