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