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Resistance of morpholino phosphorodiamidate oligomers to enzymatic degradation
R M Hudziak1, E Barofsky, D F Barofsky
1ANTIVIRALS, Inc., Corvallis, OR 97333, USA.
Abstract:
Oligomers possessing the Morpholino phosphorodiamidate backbone were evaluated for resistance to a variety of enzymes and biologic fluids. A 25-mer was incubated with nucleases, proteases, esterases, and serum, and the reaction mixtures were directly analyzed by MALDI-TOF mass spectrometry. The 25-mer was completely resistant to 13 different hydrolases and serum and plasma. The excellent resistance of Morpholino phosphorodiamidates to enzymatic attack indicates their suitability for in vivo use.
Insights
Morpholino phosphorodiamidate oligomers show excellent resistance to enzymatic degradation and biologic fluids. This stability suggests their potential for in vivo applications in therapeutic development.
Area of Science:
- Biochemistry
- Oligonucleotide Chemistry
Background:
- Oligonucleotides are crucial in therapeutics but susceptible to enzymatic degradation.
- Morpholino phosphorodiamidate backbones offer an alternative to traditional nucleic acid structures.
Purpose of the Study:
- To evaluate the enzymatic and biologic fluid resistance of Morpholino phosphorodiamidate oligomers.
- To assess the stability of these oligomers for potential in vivo applications.
Main Methods:
- A 25-mer Morpholino phosphorodiamidate oligomer was synthesized.
- Incubation with various hydrolases (nucleases, proteases, esterases) and biologic fluids (serum, plasma).
- Direct analysis of reaction mixtures using MALDI-TOF mass spectrometry.
Main Results:
- The 25-mer demonstrated complete resistance to 13 different hydrolases.
- No degradation was observed when incubated with serum and plasma.
- MALDI-TOF MS confirmed the integrity of the oligomer post-incubation.
Conclusions:
- Morpholino phosphorodiamidate backbones exhibit exceptional stability against enzymatic hydrolysis.
- This inherent resistance makes them highly suitable candidates for in vivo therapeutic applications.
- Further development of Morpholino-based therapeutics is warranted based on their stability profile.