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RESEARCH ARTICLE
Contents Vol 73(4)

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

Eduardo F. A. Fernandes A , Linda M. Haugaard-Kedström A and Kristian Strømgaard https://orcid.org/0000-0003-2206-4737 A B
+ Author Affiliations
- Author Affiliations

A Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

B Corresponding author. Email: kristian.stromgaard@sund.ku.dk

Australian Journal of Chemistry 73(4) 307-311 https://doi.org/10.1071/CH19392
Submitted: 12 August 2019  Accepted: 18 September 2019   Published: 7 November 2019

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.


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