📷Abstract:Phosphorodiamidatemorpholino oligonucleotides (PMOs)1
are routinely used for gene silencing and recently developed PMO-based drugs Exondys51 and Vyondys53 have highlighted the importance of PMO as excellent antisense reagents. However, the synthesis and delivery of PMO has remained challenging. Here a method for the synthesis of PMO using either trityl or Fmoc-protected active morpholino monomers using chlorophosphoramidate chemistry in the presence of a suitable coupling agent on a solid support has been discussed. ETT was found to be suitable for efficient coupling. Synthesis of PMO using Fmoc-chemistry is reported for the first time2. 25-mer PMO has been synthesized and validated in zebrafish model by targeting the no tail gene. Methods have been transferred in DNA synthesizer which has become user friendly for PMO synthesis. Fmoc chemistry could be suitable for scalable approach of PMO synthesis using peptide synthesizer as it is a neutral oligomer like peptide.
For the delivery of PMO, a nonpeptidic internal guanidinium transporter (IGT)3,4 has been developed and IGT-PMO conjugate was synthesized to target NANOG for inhibition which is over expressed in different cancers.
Together this technology has opened a new avenue to explore PMOs for various applications targeting numerous genes towards the development of personalized medicines.
References
1. Summerton, J. E. (2017) Invention and Early History of Morpholinos: From Pipe Dream to Practical Products. Methods Mol.Biol.1565, 1−15.
2. Kundu, J., Ghosh, U., Ghosh, A., Das, A., Nagar, D., Ghose, A., and Sinha, S.: Synthesis of Phosphorodiamidate Morpholino Oligonucleotides Using Trityl and Fmoc Chemistry-A New Method Amenable to Automated Synthesizer. ChemRxiv 2020, 10.26434/chemrxiv.12765563
3. Bhadra, J., Pattanayak, S., Khan, P. P., Kundu, J., and Sinha, S. (2016) Internal Oligoguanidinium-Based Cellular Transporter Enhances Antisense Efficacy of Morpholinos in In Vitro and Zebrafish Model. Bioconjugate Chem. 27, 2254−2259.

Synthesis and Delivery of Phosphorodiamidatemorpholino Oligonucleotides

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