RT Journal Article
T1 A non-hydrolysable peptidomimetic for mitochondrial targeting
A1 Folgar Cameán, Yeray
A1 Torralba-Maldonado, Daniel
A1 Fulias-Guzmán, Patricia
A1 Pazo, Marta
A1 Máximo-Moreno, Irene
A1 Royo, Miriam
A1 Illa, Ona
A1 Montenegro García, Javier
AB Peptidomimetics, molecules that mimic the activity of natural peptides with improved stability or bioavailability, have emerged as interesting materials with applications in biomedicine. In this study, we describe a hybrid γ,γ-peptidomimetic that efficiently aims at mitochondria, a key therapeutic target associated with several disorders, in living cells. Peptide backbones with a component of cationic and hydrophobic amino acids have been shown to preferentially target mitochondria due to their high negative membrane potential and hydrophobic character of the membranous invaginations of these key organelles. We here exploit the advantageous bioorthogonal properties of a peptidomimetic scaffold that consists of an alternation of (1S,3R)-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and an Nα-functionalised cis-γ-amino-L-proline derivative. This peptidomimetic exhibited excellent membrane translocation efficiency, mitochondrial targeting ability, and biocompatibility. Mitochondrial targeting was confirmed to be dependent on the electrochemical potential generated by the electron transport chain. The presence of non-natural amino acids rendered the compound exceptionally stable in the presence of proteases, maintaining its integrity and functionality for targeting the organelle even after 1 week of incubation in serum. This stability, coupled with its targeting abilities and the low cytosolic/endosomal residual signal, facilitated the tracking of relevant mitochondrial dynamics, including fission events and intracellular movement. Additionally, this peptidomimetic scaffold allowed the sustained and precise mitochondrial targeting of a pH sensitive ratiometric probe, 5(6)-carboxy-SNARF-1, which enabled mitochondrial pH monitoring. In summary, our study introduces a biomimetic peptide with exceptional mitochondria-targeting properties, ensuring stability in biological media and offering insights into crucial mitochondrial processes.
PB Royal Society of Chemistry
SN 2050-750X
YR 2025
FD 2025-01
LK https://hdl.handle.net/10347/42127
UL https://hdl.handle.net/10347/42127
LA eng
NO Folgar-Cameán, Y., Torralba-Maldonado, D., Fulias-Guzmán, P., Pazo, M., Máximo-Moreno, I., Royo, M., Illa, O., & Montenegro, J. (2025). A non-hydrolysable peptidomimetic for mitochondrial targeting. "Journal Of Materials Chemistry B", 13(10), 3365-3373. https://doi.org/10.1039/d4tb01626b
NO J. M. thanks the Spanish AEI (PCI2019-103400, PID2020-117143RB-I00, and PID2023-152181OB-I00), the Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2023–2027, ED431G 2023/03, and ED431F 2023/12, the Oportunius Program (GAIN)), and the European Regional Development Fund (ERDF). Y. F.-C. and P. F.-G. thank AEI (FPU21/04747; PRE2021-096972) and M. P. and I. M.-M. thank Xunta de Galicia (ED481A-2017/142 and ED481A-2024-049) for their predoctoral fellowships. D. T.-M. thanks the Generalitat de Catalunya for his predoctoral FI-SDUR fellowship (2020 FISDUR 00055). O. I. and D. T.-M. are grateful for the financial support of the Spanish AEI (PID2022-139826OB-I00) and the Generalitat de Catalunya (2020 FI-SDUR 00055). M. R. acknowledges support from CIBER BBN(CB06/01/0074) and the Generalitat de Catalunya (2021SGR00230). All authors thank Dr Irene Lostalé-Seijo for her assistance and comments. The authors would like to thank Rebeca Menaya-Vargas for her technical assistance in the maintenance of cell lines. The table of contents and Fig. 1(A) contain elements created with https://BioRender.com.
DS Minerva
RD 28 abr 2026