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Fully automated fast-flow synthesis of antisense phosphorodiamidate morpholino oligomers


Li, Chengxi; Callahan, Alex J; Simon, Mark D; Totaro, Kyle A; Mijalis, Alexander J; Phadke, Kruttika-Suhas; Zhang, Genwei; Hartrampf, Nina; Schissel, Carly K; Zhou, Ming; Zong, Hong; Hanson, Gunnar J; Loas, Andrei; Pohl, Nicola L B; Verhoeven, David E; Pentelute, Bradley L (2021). Fully automated fast-flow synthesis of antisense phosphorodiamidate morpholino oligomers. Nature Communications, 12:4396.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > General Chemistry
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Physical Sciences > General Physics and Astronomy
Uncontrolled Keywords:General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry
Language:English
Date:1 December 2021
Deposited On:15 Feb 2022 14:03
Last Modified:27 May 2024 01:53
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-021-24598-4
PubMed ID:34285203
Project Information:
  • : FunderKoch Institute MIT School of Science Fellowship in Cancer Research
  • : Grant ID
  • : Project Title
  • : FunderSarepta Therapeutics, Inc.
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)