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BioMed Research International - Volume 2014 2014, Article ID 901617, 15 pages -

Research Article

Dipartimento Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy

Dipartimento di Chimica Farmaceutica e Tossicologica, Università “Federico II,” Via D. Montesano 49, 80131 Napoli, Italy

Received 10 December 2013; Accepted 23 January 2014; Published 26 March 2014

Academic Editor: Daniela De Stefano

Copyright © 2014 Maria Gaglione et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The active components of the RNAi are 21 nucleotides long dsRNAs containing a 2 nucleotide overhang at the 3′ end, carrying 5′-phosphate and 3′-hydroxyl groups siRNAs. Structural analysis revealed that the siRNA is functionally bound at both ends to RISC. Terminal modifications are considered with interest as the introduction of chemical moieties interferes with the 3′ overhang recognition by the PAZ domain and the 5′-phosphate recognition by the MID and PIWI domains of RISC. Herein, we report the synthesis of modified siRNAs containing terminal amide linkages by introducing hydroxyethylglycine PNA hegPNA moieties at 5′, and at 3′ positions and on both terminals. Results of gene silencing studies highlight that some of these modifications are compatible with the RNAi machinery and markedly increase the resistance to serum-derived nucleases even after 24 h of incubation. Molecular docking simulations were attained to give at atomistic level a clearer picture of the effect of the most performing modifications on the interactions with the human Argonaute 2 PAZ, MID, and PIWI domains. This study adds another piece to the puzzle of the heterogeneous chemical modifications that can be attained to enhance the silencing efficiency of siRNAs.





Autor: Maria Gaglione, M. Emilia Mercurio, Nicoletta Potenza, Nicola Mosca, Aniello Russo, Ettore Novellino, Sandro Cosconati, and

Fuente: https://www.hindawi.com/



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