Organosilicon molecules bind to the intrinsically disordered protein NUPR1 by clamping its hot-spots
Peña, Laura F. ; Estaras, Matías ; González-Andrés, Paula ; Díez-Poza, Carlos ; Rizzuti, Bruno ; Abian, Olga (Universidad de Zaragoza) ; Velazquez-Campoy, Adrian (Universidad de Zaragoza) ; Iovanna, Juan L. ; Santofimia-Castaño, Patricia ; Neira, José L. ; Barbero, Asunción
Resumen: The nuclear protein 1, or NUPR1, is an intrinsically disordered protein (IDP) involved in the development and progression of pancreatic ductal adenocarcinoma (PDAC). We have previously developed drugs capable of binding at the two hot-spot regions of NUPR1, around residues Ala33 and Thr68, hampering its interactions in cellulo. In this work, we synthesized new organosilicon molecules targeting those key hot-spots. The compounds were obtained by an acid-catalyzed intramolecular cyclization of a starting alkenol that contains a silyl group attached to the double bond. Binding between the silyl compounds and NUPR1 involved the two hot-spots, as shown by 2D 1H–15N HSQC NMR. Molecular simulations clarified that the binding relies on a loose clamp mechanism of the ligands towards the hot-spots. The dissociation constants (Kd) were around 20 μM, as measured by several biophysical techniques. However, studies in cellulo with PDAC cells did not show a decrease of cell viability upon treatment with the compounds; furthermore, proximity ligation assays in cellulo with a natural partner protein of NUPR1, G3BP, did not show a significant level of interfering in such interaction when silyl compounds were present, probably due to the high hydrophobicity of the designed compounds. Thus, in the case of NUPR1, moderate-to-high drug binding affinities (Kd < 10 μM) in vitro and a higher hydrophilicity are necessary to hamper protein-protein interactions in cellulo. As a more general conclusion, in vitro binding of ligands to the protein hot-spots is a necessary condition in the drug design targeting IDPs, but it is not enough to guarantee inhibition of their interactions in cellulo.
Idioma: Inglés
DOI: 10.1016/j.abb.2025.110513
Año: 2025
Publicado en: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 771 (2025), 110513 [12 pp.]
ISSN: 0003-9861
Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-23R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI18-0394
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
Tipo y forma: Article (Published version)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes.
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Idioma: Inglés
DOI: 10.1016/j.abb.2025.110513
Año: 2025
Publicado en: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 771 (2025), 110513 [12 pp.]
ISSN: 0003-9861
Financiación: info:eu-repo/grantAgreement/ES/DGA/B25-23R
Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-23R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI18-0394
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
Tipo y forma: Article (Published version)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. Exportado de SIDERAL (2025-10-17-14:17:07)
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Record created 2025-07-17, last modified 2025-10-17