Kinetic and thermodynamic properties of phosphorothioate and phosphorodiamidate morpholino oligonucleotides binding to target RNA
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ID: 317816
2026
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Abstract
Recently, numerous nucleic acid therapeutics have been developed, and a substantial number of the approved agents are categorized as antisense oligonucleotides (ASOs). These therapeutics comprise phosphorothioate oligonucleotide (PS-DNA) or phosphorodiamidate morpholino oligonucleotide (PMO) featuring chemically modified nucleic acid backbones for nuclease resistance. Although chemical modifications to the backbone and sugar moieties of ASOs enhance nuclease resistance, increase binding affinity toward target RNAs, and optimize pharmacokinetic properties, information on the physicochemical properties of ASO therapeutics, which are mixtures of several stereoisomers, remains limited. In this study, the physicochemical properties of PS-DNA and PMO were analyzed using ultraviolet melting analysis, surface plasmon resonance, isothermal titration calorimetry, and nuclear magnetic resonance. Compared with natural deoxynucleotide, PS-DNA more rapidly dissociates from the complementary RNA, resulting in a lower RNA affinity, whereas PMO more quickly associates with the complementary RNA, leading to a higher RNA affinity. Furthermore, characteristic thermodynamic parameters governing the binding of PMO to RNA were determined. Although these physicochemical properties of ASOs are derived from a single model system, the accumulation of physicochemical data for ASOs featuring various sequences and lengths will contribute to the future development of nucleic acid-based therapeutics.
| Reference Key |
openalex_W7165149018
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| Authors | Takuya Hasegawa, Kazuki Sato, Hiroya Kuwahara, Takeshi Wada, Taiichi Sakamoto |
| Journal | The Journal of Biochemistry |
| Year | 2026 |
| DOI |
10.1093/jb/mvag043
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| URL | |
| Keywords | Keywords not found |
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