KDEL-mediated modulation of intracellular trafficking in cell-targeted protein drugs
Voltà-Durán, Eric (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Alba Castellón, Lorena (Institut de Recerca Sant Pau)
Arena, Lourdes Ailen (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Sanchez, Julieta M. (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Casanova Rigat, Isolda (Institut de Recerca Sant Pau)
Mangues, Ramon 1957- (Institut de Recerca Sant Pau)
Villaverde Corrales, Antonio (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Vázquez Gómez, Esther (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Unzueta Elorza, Ugutz (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)

Date:	2026
Abstract:	The biological activity of therapeutic proteins, upon intracellular delivery, is dramatically minimized by lysosomal proteolytic digestion. This is a limitation when developing cell-targeted pharmaceuticals that penetrate target cells via receptor recognition and endosomal engulfment. Since proteins benefit from functional and conformational versatility, editable by genetic engineering, endosomolytic protein domains are often fused to the functional polypeptide to promote their cytosolic delivery, aiming at minimizing proteolysis in mature lysosomes. This straightforward strategy has, however, rendered irregular results, linked to the fusogenic nature of most of the tested domains. Alternatively, proteolysis of protein drugs might be controlled by bypassing the lysosomal route, forcing an unconventional traffic of the uptaken protein material to be secreted from the endoplasmic reticulum (ER). This possibility, used in nature by several plant and microbial proteins, has been evaluated here by functionalizing a protein-only antitumoral drug, based on a cell-targeted diphtheria toxin, with a C-terminal KDEL motif. Thus, if KDEL were able to reprogram the intracellular trafficking, KDEL-tagged cell delivered proteins would be expected to avoid the lysosomal degradation, resulting in enhanced stability and activity. The obtained results validate this hypothesis and point out KDEL as a promising functional agent in cell-targeted protein drugs.
Grants:	Agencia Estatal de Investigación PDC2022-133858-I00 Agencia Estatal de Investigación PID2022-136845OB-I00 Agencia Estatal de Investigación PID2020-116174RB-I00 Agencia Estatal de Investigación CNS2024-154280 Generalitat de Catalunya 2021/SGR-00092 Generalitat de Catalunya 2021/SGR-01140 Instituto de Salud Carlos III PI24/01476 Instituto de Salud Carlos III PI20/00400 Instituto de Salud Carlos III PI23/00318 Ministerio de Ciencia, Innovación y Universidades FPU18/04615 Instituto de Salud Carlos III CP19/00028 "la Caixa" Foundation 12070029 Instituto de Salud Carlos III CP24/00111 Ministerio de Sanidad y Consumo CB06/01/0014 Ministerio de Sanidad y Consumo CB06/01/1031
Note:	Altres ajuts: acords transformatius de la UAB
Note:	Altres ajuts: CERCA Programme/Generalitat de Catalunya; AECC (POSTD20070ALBA); María Zambrano postdoctoral researcher contract (677904) from Ministerio de Universidades and European Union (financed by European Union-Next GenerationEU)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Protein engineering ; Targeted drug delivery ; Protein drugs
Published in:	European Journal of Pharmaceutics and Biopharmaceutics, Vol. 222 (May 2026) , art. 115020, ISSN 1873-3441

DOI: 10.1016/j.ejpb.2026.115020

8 p, 3.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles