000162158 001__ 162158
000162158 005__ 20251017144610.0
000162158 0247_ $$2doi$$a10.1016/j.abb.2025.110513
000162158 0248_ $$2sideral$$a144747
000162158 037__ $$aART-2025-144747
000162158 041__ $$aeng
000162158 100__ $$aPeña, Laura F.
000162158 245__ $$aOrganosilicon molecules bind to the intrinsically disordered protein NUPR1 by clamping its hot-spots
000162158 260__ $$c2025
000162158 5060_ $$aAccess copy available to the general public$$fUnrestricted
000162158 5203_ $$aThe 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.
000162158 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B25-23R$$9info:eu-repo/grantAgreement/ES/DGA/E45-23R$$9info:eu-repo/grantAgreement/ES/ISCIII/PI18-0394$$9info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00
000162158 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttps://creativecommons.org/licenses/by-nc/4.0/deed.es
000162158 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000162158 700__ $$aEstaras, Matías
000162158 700__ $$aGonzález-Andrés, Paula
000162158 700__ $$aDíez-Poza, Carlos
000162158 700__ $$aRizzuti, Bruno
000162158 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza
000162158 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrian$$uUniversidad de Zaragoza
000162158 700__ $$aIovanna, Juan L.
000162158 700__ $$aSantofimia-Castaño, Patricia
000162158 700__ $$aNeira, José L.
000162158 700__ $$aBarbero, Asunción
000162158 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000162158 773__ $$g771 (2025), 110513 [12 pp.]$$pArch. biochem. biophys.$$tARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS$$x0003-9861
000162158 8564_ $$s6467967$$uhttps://zaguan.unizar.es/record/162158/files/texto_completo.pdf$$yVersión publicada
000162158 8564_ $$s2673162$$uhttps://zaguan.unizar.es/record/162158/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000162158 909CO $$ooai:zaguan.unizar.es:162158$$particulos$$pdriver
000162158 951__ $$a2025-10-17-14:17:07
000162158 980__ $$aARTICLE