TY - CHAP

T1 - Mesyl Phosphoramidate Oligonucleotides: A New Promising Type of Antisense Agents

AU - Stetsenko, Dmitry A.

N1 - Author would like to thank Dr. Vyacheslav V. Filichev (Massey University, New Zealand) for CD spectra and Dr. B.P. Chelobanov (Novosibirsk State University) for confocal microscopy. This work was funded by the Ministry of Science and Higher Education of the Russian Federation (project of Novosibirsk State University No. FSUS-2020-0035).

PY - 2023/1/1

Y1 - 2023/1/1

N2 - This chapter provides an overview of mesyl phosphoramidate oligonucleotides (μ-oligonucleotides), which incorporate mesyl phosphoramidate groups (MsPA , or μ) instead of natural phosphate linkages up to the complete replacement at all internucleotidic positions. μ-Oligonucleotides can be efficiently obtained by β-cyanoethyl phosphoramidite chemistry via substituting Staudinger reaction of the intermediate phosphite triester with methanesulfonyl azide for conventional iodine oxidation of P(III) to P(V) in an automatic DNA/RNA synthesizer. The MsPA group is negatively charged under near physiological conditions around pH 7 and, according to circular dichroism spectra of the corresponding duplexes with DNA or RNA, represents a close phosphodiester bond mimic. Thermal melting studies and gel shift experiments confirmed the affinity of μ-oligodeoxynucleotides to RNA as only slightly lower than that of the natural DNA, and similar or better than that of phosphorothioate (PS) oligonucleotides. Uniform MsPA modification conveyed to oligonucleotides the exceptional nuclease resistance exceeding that of PS group. Importantly for potential antisense therapeutic application, the duplexes of μ-oligodeoxynucleotides with complementary RNAs are the substrates for RNase H. The data obtained until recently suggest that oligonucleotide modification with MsPA (μ) groups for antisense studies results in the decrease of in vivo toxicity and increase of the duration of the biological effect while preserving or even enhancing the overall potency. Therefore, mesyl phosphoramidate oligonucleotides can be considered as a promising new type of RNase H recruiting antisense agents either as mixed backbone oligomers, preferably gapmers, incorporating both phosphorothioate and MsPA linkages at the same time, or as purely μ-oligonucleotides having only MsPA groups at all internucleotidic positions if delivered by in vivo compatible cationic liposomes.

AB - This chapter provides an overview of mesyl phosphoramidate oligonucleotides (μ-oligonucleotides), which incorporate mesyl phosphoramidate groups (MsPA , or μ) instead of natural phosphate linkages up to the complete replacement at all internucleotidic positions. μ-Oligonucleotides can be efficiently obtained by β-cyanoethyl phosphoramidite chemistry via substituting Staudinger reaction of the intermediate phosphite triester with methanesulfonyl azide for conventional iodine oxidation of P(III) to P(V) in an automatic DNA/RNA synthesizer. The MsPA group is negatively charged under near physiological conditions around pH 7 and, according to circular dichroism spectra of the corresponding duplexes with DNA or RNA, represents a close phosphodiester bond mimic. Thermal melting studies and gel shift experiments confirmed the affinity of μ-oligodeoxynucleotides to RNA as only slightly lower than that of the natural DNA, and similar or better than that of phosphorothioate (PS) oligonucleotides. Uniform MsPA modification conveyed to oligonucleotides the exceptional nuclease resistance exceeding that of PS group. Importantly for potential antisense therapeutic application, the duplexes of μ-oligodeoxynucleotides with complementary RNAs are the substrates for RNase H. The data obtained until recently suggest that oligonucleotide modification with MsPA (μ) groups for antisense studies results in the decrease of in vivo toxicity and increase of the duration of the biological effect while preserving or even enhancing the overall potency. Therefore, mesyl phosphoramidate oligonucleotides can be considered as a promising new type of RNase H recruiting antisense agents either as mixed backbone oligomers, preferably gapmers, incorporating both phosphorothioate and MsPA linkages at the same time, or as purely μ-oligonucleotides having only MsPA groups at all internucleotidic positions if delivered by in vivo compatible cationic liposomes.

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85194022757&origin=inward&txGid=a139c768c13903d4731ddf5787287186

UR - https://www.mendeley.com/catalogue/50b9344f-3aa9-3718-8497-fecdd257de6d/

U2 - 10.1007/978-981-16-1313-5_19-1

DO - 10.1007/978-981-16-1313-5_19-1

M3 - Chapter

SN - 978-981-16-1313-5

T3 - Handbook of Chemical Biology of Nucleic Acids

SP - 543

EP - 583

BT - Handbook of Chemical Biology of Nucleic Acids

A2 - Sugimoto, Naoki

PB - Springer Nature Singapore

ER -