Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases. PMOs (phosphorodiamidate morpholino oligomers) have huge potential for antisense therapy but complex and slow synthesis limits application. Here, the authors report the development of automated flow synthesis methods which reduce nucleobase coupling times from hours to minutes removing human errors and allow for high-throughput production.
【저자키워드】 Automation, nucleic acids, Flow chemistry, Solid-phase synthesis, Synthetic chemistry methodology, 【초록키워드】 SARS-CoV-2, therapy, Diseases, antiviral effects, mRNA, response, Personalized medicine, therapeutic, Rapid, target, automated, genomic, platform, antisense, drug candidates, complex, sequence, candidate, treat, viral pathogen, genetic disease, oligomers, widespread, DMD, limit, new SARS-CoV-2, oligomer, reported, reduce, muscular, 【제목키워드】 automated, oligomer,