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

Bioorg Med Chem. 2024 Jan 28;100:117616. doi: 10.1016/j.bmc.2024.117616. Online ahead of print.ABSTRACTHerein, we report the synthesis of 2'-O-alkyl/2'-fluoro-N3-methyluridine (2'-O-alkyl/2'-F-m3U) 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-m3U modifications significantly decreased the thermal stability and base-pairing discrimination ability. Serum stability study of dT20 with 2'-O-alkyl-m3U modification exhibited excellent nuclease resistance when incubated with 3'-exonucleases (SVPD) or 5'-exonucleases (PDE-II) as compared to m3U, 2'-F, 2'-OMe modified oligonucleotides. MD simulation studies with RNA tetradecamer duplexes illustrated that the m3U and 2'-O-methyl-m3U 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-m3U 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-m3U nucleotides can be used as a promising tool to enhance the stability, silencing efficiency, and drug-like properties of antisense/siRNA-based therapeutics.PMID:38295488 | DOI:10.1016/j.bmc.2024.117616

Source: Bioorganic and Medicinal Chemistry - January 31, 2024 Category: Chemistry Authors: Avijit Sahoo Gourav Das Atanu Ghosh Siddharam Shivappa Bagale Nishant Kumar Choudhary S Harikrishna Surajit Sinha Kiran R Gore Source Type: research