N 3 -Methyluridine and 2'-O-Alkyl/2'-Fluoro-N 3 -methyluridine functionalized nucleic acids improve nuclease resistance while maintaining duplex geometry.

Autor: Sahoo A; Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302, India., Das G; Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302, India., Ghosh A; School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India., Shivappa Bagale S; Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India., Kumar Choudhary N; Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302, India., Harikrishna S; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, United States., Sinha S; School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India., Gore KR; Department of Chemistry, Indian Institute of Technology Kharagpur, West Bengal 721302, India. Electronic address: kiran@chem.iitkgp.ac.in.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Feb 15; Vol. 100, pp. 117616. Date of Electronic Publication: 2024 Jan 28.
DOI: 10.1016/j.bmc.2024.117616
Abstrakt: Herein, we report the synthesis of 2'-O-alkyl/2'-fluoro-N 3 -methyluridine (2'-O-alkyl/2'-F-m 3 U) phosphoramidites and their incorporation in DNA and RNA oligonucleotides. The duplex binding affinity and base discrimination studies showed that all 2'-O-alkyl/2'-F-m 3 U modifications significantly decreased the thermal stability and base-pairing discrimination ability. Serum stability study of dT 20 with 2'-O-alkyl-m 3 U modification exhibited excellent nuclease resistance when incubated with 3'-exonucleases (SVPD) or 5'-exonucleases (PDE-II) as compared to m 3 U, 2'-F, 2'-OMe modified oligonucleotides. MD simulation studies with RNA tetradecamer duplexes illustrated that the m 3 U and 2'-O-methyl-m 3 U modifications reduce the duplex stabilities by disrupting the Watson-Crick hydrogen bonding and base-stacking interactions. Further molecular modelling investigations demonstrated that the 2'-O-propyl-m 3 U modification exhibits steric interactions with amino acid residues in the active site of 3'- and 5'-exonuclease, leading to enhanced stability. These combined data indicate that the 2'-modified-m 3 U nucleotides can be used as a promising tool to enhance the stability, silencing efficiency, and drug-like properties of antisense/siRNA-based therapeutics.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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