The Effects of Lipidation on a TAT-Containing Peptide-Based Inhibitor of PSD-95

Stability and cell permeability are critical parameters in the development of peptide therapeutics. Conjugation to fatty acids and cell-penetrating peptides, such as TAT (YGRKKRRQRRR), are established strategies to increase peptide stability and permeation, respectively. Here, we prepared lipidated analogues of a potent TAT-containing dimeric peptidebased inhibitor of the intracellular scaffolding protein PSD-95, an emerging drug target in ischaemic stroke. Lipidation increased peptide stability in vitro and in vivo. Combining both lipidation and conjugation to TAT improved brain/plasma ratios, but caused acute toxic effects due to the potent haemolytic activity of the TAT-lipid moiety.