Fully automated fast-flow synthesis of antisense phosphorodiamidate morpholino oligomers.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34285203.
- Also identified by DOI 10.1038/s41467-021-24598-4 and PMC identifier 8292409.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Chemistry Techniques, Synthetic
- Chemistry, Pharmaceutical
- High-Throughput Screening Assays
- Morpholinos
- Oligonucleotides, Antisense