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Thermodynamic Destabilization and Structural Adaptability of 2′-Alkoxy/Fluoro-N3-Methyl Pyrimidine Nucleotides in siRNA Enhance RNA Interference Activity

2025/07/30 by Avijit Sahoo, Shalini Gupta, Gourav Das +5
Biochemistry, Genetics and Molecular Biology · #DNA and Nucleic Acid Chemistry #RNA Interference and Gene Delivery #RNA and protein synthesis mechanisms

paper · doi:10.1021/acs.jmedchem.5c01269

Abstract

U at g7 as a seed mismatch, alone or in combination with a modified passenger strand, preserved silencing efficacy. Furthermore, these modifications displayed no adverse immunostimulatory response, maintaining bioavailability and preventing cytotoxicity. Molecular modeling studies focused on the g7 position within the MID domain of hAgo2 provided insights into the structural tolerance of these modifications and their role in modulating target mRNA binding affinity, thereby influencing RNAi activity.

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