Perfluoroarene–Based
Peptide Macrocycles to
Enhance Penetration Across the Blood–Brain Barrier
Colin
M. Fadzen
Justin M. Wolfe
Choi-Fong Cho
E. Antonio Chiocca
Sean E. Lawler
Bradley L. Pentelute
10.1021/jacs.7b09790.s001
https://acs.figshare.com/articles/journal_contribution/Perfluoroarene_Based_Peptide_Macrocycles_To_Enhance_Penetration_across_the_Blood_Brain_Barrier/5550307
Here
we describe the utility of peptide macrocyclization through
perfluoroaryl-cysteine S<sub>N</sub>Ar chemistry to improve the ability
of peptides to cross the blood–brain barrier. Multiple macrocyclic
analogues of the peptide transportan-10 were investigated that displayed
increased uptake in two different cell lines and improved proteolytic
stability. One of these analogues (M13) exhibited substantially increased
delivery across a cellular spheroid model of the blood–brain
barrier. Through <i>ex vivo</i> imaging of mouse brains,
we demonstrated that this perfluoroarene-based macrocycle of TP10
exhibits increased penetration of the brain parenchyma following intravenous
administration in mice. Finally, we evaluated macrocyclic analogues
of the BH3 domain of the BIM protein to assess if our approach would
be applicable to a peptide of therapeutic interest. We identified
a BIM BH3 analogue that showed increased penetration of the brain
tissue in mice.
2017-10-09 00:00:00
BH 3 domain
vivo imaging
brain parenchyma
brain tissue
Multiple macrocyclic analogues
peptide macrocyclization
perfluoroaryl-cysteine S N Ar chemistry
barrier
peptide transportan -10
penetration
BIM protein
spheroid model
BIM BH 3 analogue
Enhance Penetration
macrocyclic analogues
perfluoroarene-based macrocycle
mouse brains
TP 10 exhibits
cell lines