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- Title
The Effects of Lipidation on a TAT-Containing Peptide-Based Inhibitor of PSD-95.
- Authors
Fernandes, Eduardo F. A.; Haugaard-Kedström, Linda M.; Strømgaard, Kristian
- Abstract
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 peptide-based 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. We synthesised and evaluated combining lipidation and conjugation to the cell-penetrating peptide TAT to increase peptide stability and brain permeability in vivo. Even though TAT–lipid combinations were stable in vivo and in vitro and permeated to the brain, they were haemolytic and resulted in acute toxic effects in vivo.
- Subjects
ISOPRENYLATION; CELL-penetrating peptides; SCAFFOLD proteins; CELL permeability; FATTY acids
- Publication
Australian Journal of Chemistry, 2020, Vol 73, Issue 4, p307
- ISSN
0004-9425
- Publication type
Article
- DOI
10.1071/CH19392