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https://hdl.handle.net/10316/107535
Título: | Exploring PAZ/3′-overhang interaction to improve siRNA specificity. A combined experimental and modeling study | Autor: | Alagia, Adele Jorge, Andreia F. Aviñó, Anna Cova, Tânia F. G. G. Crehuet, Ramon Grijalvo, Santiago Pais, Alberto Eritja, Ramon |
Data: | 2018 | Editora: | Royal Society of Chemistry | Projeto: | Spanish Ministerio de Ciencia e Innovaci´on (MICINN) (Projects CTQ2014-52588-R CTQ2017-84415-R and CTQ2016-78636-P) Generalitat de Catalunya FCT - Post-Doctoral grant SFRH/BPD/104544/2014 FCT - PhD grant SFRH/BD/95459/2013 PEst-OE/QUI/UI0313/2014 POCI-01-0145- FEDER-007630 CIBER-BBN is an initiative funded by the VI National R + D + I Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and nanced by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund |
Título da revista, periódico, livro ou evento: | Chemical Science | Volume: | 9 | Número: | 8 | Resumo: | The understanding of the dynamical and mechanistic aspects that lie behind siRNA-based gene regulation is a requisite to boost the performance of siRNA therapeutics. A systematic experimental and computational study on the 30-overhang structural requirements for the design of more specific and potent siRNA molecules was carried out using nucleotide analogues differing in structural parameters, such as sugar constraint, lack of nucleobase, distance between the phosphodiester backbone and nucleobase, enantioselectivity, and steric hindrance. The results established a set of rules governing the siRNAmediated silencing, indicating that the thermodynamic stability of the 50-end is a crucial determinant for antisense-mediated silencing but is not sufficient to avoid sense-mediated silencing. Both theoretical and experimental approaches consistently evidence the existence of a direct connection between the PAZ/30-overhang binding affinity and siRNA’s potency and specificity. An overall description of the systems is thus achieved by atomistic simulations and free energy calculations that allow us to propose a robust and self-contained procedure for studying the factors implied in PAZ/30-overhang siRNA interactions. A higher RNAi activity is associated with a moderate-to-strong PAZ/30-overhang binding. Contrarily, lower binding energies compromise siRNA potency, increase specificity, and favor siRNA downregulation by Ago2-independent mechanisms. This work provides in-depth details for the design of powerful and safe synthetic nucleotide analogues for substitution at the 30-overhang, enabling some of the intrinsic siRNA disadvantages to be overcome. | URI: | https://hdl.handle.net/10316/107535 | ISSN: | 2041-6520 2041-6539 |
DOI: | 10.1039/C8SC00010G | Direitos: | openAccess |
Aparece nas coleções: | I&D CQC - Artigos em Revistas Internacionais |
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Ficheiro | Descrição | Tamanho | Formato | |
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Exploring-PAZ3overhang-interaction-to-improve-siRNA-specificity-A-combined-experimental-and-modeling-studyChemical-Science.pdf | 2.37 MB | Adobe PDF | Ver/Abrir |
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