Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/161765
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Exploring PAZ/3′-overhang interaction to improve siRNA specificity. A combined experimental and modeling study |
Autor: | Adagia, Adele; Jorge, Andreia F.; Aviñó, Anna CSIC ORCID; Cova, Tânia F.G.G.; Crehuet, Ramón CSIC ORCID ; Grijalvo, Santiago CSIC ORCID; Pais, Alberto A. C. C.; Eritja Casadellà, Ramón CSIC ORCID | Palabras clave: | siRNA PAZ/3′-overhang binding |
Fecha de publicación: | 15-ene-2018 | Editor: | Royal Society of Chemistry (UK) | Citación: | Chemical science | Resumen: | 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 3′-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 siRNA-mediated silencing, indicating that the thermodynamic stability of the 5′-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/3′-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/3′-overhang siRNA interactions. A higher RNAi activity is associated with a moderate-to-strong PAZ/3′-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 3′-overhang, enabling some of the intrinsic siRNA disadvantages to be overcome. | Versión del editor: | 10.1039/C8SC00010G | URI: | http://hdl.handle.net/10261/161765 | DOI: | 10.1039/C8SC00010G |
Aparece en las colecciones: | (IQAC) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Exploring PAZ 30 overhang interaction to improve.pdf | 2,28 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
WEB OF SCIENCETM
Citations
16
checked on 02-feb-2024
Page view(s)
285
checked on 18-abr-2024
Download(s)
290
checked on 18-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.