Multivalent peptides for blood–brain barrier translocation, cell penetration and microRNA-21 inhibition in glioblastoma
5 affiliations
- 1School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University Liverpool UK
- 2Institute for Health Research, Liverpool John Moores University Liverpool UK
- 3Fundação GIMM – Gulbenkian Institute for Molecular Medicine Av. Prof Egas Moniz 1649-028 Lisboa Portugal
- 4Faculdade de Medicina, Universidade de Lisbia Av. Prof. Egas Moniz 1649-028 Lisboa Portugal
- 5EaStChem School of Chemistry, The University of Edinburgh Joseph Black Building, David Brewster Road Edinburgh EH9 3FJ UK
Abstract
Glioblastoma (GBM) is an aggressive brain cancer for which the prognosis remains poor despite the advances in our understanding of the complex heterogeneity of the disease. Therapeutic access to GBM tumours requires drugs to cross the blood–brain barrier (BBB), a physiological obstacle that restricts the passage of compounds from systemic circulation into the brain. Blood–brain barrier peptide shuttles (BBBpS), which are a subclass of cell penetrating peptides (CPPs), represent a promising approach for transferring large cargos across the BBB, especially cargos such as peptides or antisense oligonucleotides against RNA targets. Such RNA targets include microRNAs (miRNA), of which several have emerged as candidate drug targets in GBM. MicroRNA-21 is one such miRNA implicated in GBM, and although peptide-based miR-21 inhibition has been reported, delivery of peptide-based inhibitors of miR-21 across the BBB has received limited attention. Here, we selected a BBB-penetrating peptide, SYPGWSW, for conjugation to a peptide-based inihibitor of miRNA processing. We show that SYPGWSW penetrates GBM cell lines and its function depends critically on the properties of aromatic residues Tyr and Trp but not on Pro residues. Further, subsitution of Tyr with unnatural amino acids cyclohexylalanine or 1-naphthylalanine enhanced the internalisaton of the parent peptide by 2 to 4 fold. Mechanistically, the higher level of uptake was associated with enhanced stability of the peptide, which appeared to be partly associated with binding to human serum albumin. Finally we showed that a peptide inhibitor of miR-21 processing conjugated to SYPGWSW traversed an in vitro BBB model and enabled the functional silencing of miR-21-5p in GBM cells. Together, these findings pave the way for peptide conjugates as novel therapeutics for silencing miRNA expression in brain cancer.
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BibTeX
@article{chaudhry2026multivalent,
title = {{Multivalent peptides for blood–brain barrier translocation, cell penetration and microRNA-21 inhibition in glioblastoma}},
author = {Talhat Chaudhry and Marco Cavaco and Vera Neves and Miguel A. R. B. Castanho and Lauren Tonge and Francesca Giuntini and Adam Schofield and Christopher R. Coxon and Kehinde Ross},
journal = {RSC Chemical Biology},
year = {2026},
month = sep,
doi = {10.1039/d6cb00229c},
url = {https://doi.org/10.1039/d6cb00229c},
note = {CC BY 3.0},
}
RIS
TY - JOUR
TI - Multivalent peptides for blood–brain barrier translocation, cell penetration and microRNA-21 inhibition in glioblastoma
AU - Talhat Chaudhry
AU - Marco Cavaco
AU - Vera Neves
AU - Miguel A. R. B. Castanho
AU - Lauren Tonge
AU - Francesca Giuntini
AU - Adam Schofield
AU - Christopher R. Coxon
AU - Kehinde Ross
PY - 2026
DA - 2026/09/01
JO - RSC Chemical Biology
DO - 10.1039/d6cb00229c
UR - https://doi.org/10.1039/d6cb00229c
AB - Glioblastoma (GBM) is an aggressive brain cancer for which the prognosis remains poor despite the advances in our understanding of the complex heterogeneity of the disease. Therapeutic access to GBM tumours requires drugs to cross the blood–brain barrier (BBB), a physiological obstacle that restricts the passage of compounds from systemic circulation into the brain. Blood–brain barrier peptide shuttles (BBBpS), which are a subclass of cell penetrating peptides (CPPs), represent a promising approach for transferring large cargos across the BBB, especially cargos such as peptides or antisense oligonucleotides against RNA targets. Such RNA targets include microRNAs (miRNA), of which several have emerged as candidate drug targets in GBM. MicroRNA-21 is one such miRNA implicated in GBM, and although peptide-based miR-21 inhibition has been reported, delivery of peptide-based inhibitors of miR-21 across the BBB has received limited attention. Here, we selected a BBB-penetrating peptide, SYPGWSW, for conjugation to a peptide-based inihibitor of miRNA processing. We show that SYPGWSW penetrates GBM cell lines and its function depends critically on the properties of aromatic residues Tyr and Trp but not on Pro residues. Further, subsitution of Tyr with unnatural amino acids cyclohexylalanine or 1-naphthylalanine enhanced the internalisaton of the parent peptide by 2 to 4 fold. Mechanistically, the higher level of uptake was associated with enhanced stability of the peptide, which appeared to be partly associated with binding to human serum albumin. Finally we showed that a peptide inhibitor of miR-21 processing conjugated to SYPGWSW traversed an in vitro BBB model and enabled the functional silencing of miR-21-5p in GBM cells. Together, these findings pave the way for peptide conjugates as novel therapeutics for silencing miRNA expression in brain cancer.
SN - 2633-0679
ER -