New article: "KDEL-mediated modulation of intracellular trafficking in cell-targeted protein drugs"

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.

Article data:

Eric Voltà-Durán, Lorena Alba-Castellon, Lourdes A. Arena, Julieta M. Sánchez, Isolda Casanova, Ramón Mangues, Antonio Villaverde, Esther Vázquez, Ugutz Unzueta. KDEL-mediated modulation of intracellular trafficking in cell-targeted protein drugs. European Journal of Pharmaceutics and Biopharmaceutics, Volume 222, 2026, 115020, ISSN 0939-6411. https://doi.org/10.1016/j.ejpb.2026.115020.

DOI: 10.1016/j.ejpb.2026.02.002