Fully automated fast-flow synthesis of antisense phosphorodiamidate morpholino oligomers

Chengxi Li, Alex J. Callahan, Mark D. Simon, Kyle A. Totaro, Alexander J. Mijalis, Kruttika-Suhas Phadke, Genwei Zhang, Nina Hartrampf, Carly K. Schissel, Ming Zhou, Hong Zong, Gunnar J. Hanson, Andrei Loas, Nicola L. B. Pohl, David E. Verhoeven and Bradley L. Pentelute ()
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Chengxi Li: Massachusetts Institute of Technology
Alex J. Callahan: Massachusetts Institute of Technology
Mark D. Simon: Massachusetts Institute of Technology
Kyle A. Totaro: Massachusetts Institute of Technology
Alexander J. Mijalis: Massachusetts Institute of Technology
Kruttika-Suhas Phadke: Iowa State University
Genwei Zhang: Massachusetts Institute of Technology
Nina Hartrampf: Massachusetts Institute of Technology
Carly K. Schissel: Massachusetts Institute of Technology
Ming Zhou: Sarepta Therapeutics
Hong Zong: Sarepta Therapeutics
Gunnar J. Hanson: Sarepta Therapeutics
Andrei Loas: Massachusetts Institute of Technology
Nicola L. B. Pohl: Indiana University
David E. Verhoeven: Iowa State University
Bradley L. Pentelute: Massachusetts Institute of Technology

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24598-4

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