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...

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Bibliographic Details
Published inAustralian journal of chemistry Vol. 73; no. 4; p. 307
Main Authors Fernandes, Eduardo F. A., Haugaard-Kedström, Linda M., Strømgaard, Kristian
Format Journal Article
LanguageEnglish
Published Collingwood CSIRO 01.01.2020
Subjects
Amino acids
Biocompatibility
Conjugation
Fatty acids
Inhibitors
Ischemia
Lipids
Peptides
Pharmacokinetics
Plasma
Proteins
Scaffolding
Stability
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Summary: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.
ISSN:0004-9425
1529-5036
DOI:10.1071/CH19392