Design, synthesis, and characterization of fatty acid derivatives of a dimeric peptide-based postsynaptic density-95 (PSD-95) inhibitor

Klaus B Nissen; Julie J Andersen; Linda M Haugaard-Kedström; Anders Bach; Kristian Strømgaard

doi:10.1021/jm501755d

Design, synthesis, and characterization of fatty acid derivatives of a dimeric peptide-based postsynaptic density-95 (PSD-95) inhibitor

J Med Chem. 2015 Feb 12;58(3):1575-80. doi: 10.1021/jm501755d. Epub 2015 Jan 30.

Authors

Klaus B Nissen¹, Julie J Andersen, Linda M Haugaard-Kedström, Anders Bach, Kristian Strømgaard

Affiliation

¹ Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.

PMID: 25590984
DOI: 10.1021/jm501755d

Abstract

Dimeric peptide-based inhibitors of postsynaptic density-95 (PSD-95) can reduce ischemic brain damage and inflammatory pain in rodents. To modify the pharmacokinetic profile, we designed a series of fatty acid linked dimeric ligands, which potently inhibits PSD-95 and shows improved in vitro blood plasma stability. Subcutaneous administration in rats showed extended stability and sustained release of these ligands. This can facilitate new pharmacological uses of PSD-95 inhibitors and further exploration of PSD-95 as a drug target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disks Large Homolog 4 Protein
Dose-Response Relationship, Drug
Drug Design*
Fatty Acids / chemical synthesis
Fatty Acids / chemistry
Fatty Acids / pharmacology*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Ligands
Membrane Proteins / antagonists & inhibitors*
Molecular Structure
Peptides / chemistry*
Rats
Structure-Activity Relationship

Substances

Disks Large Homolog 4 Protein
Dlg4 protein, rat
Fatty Acids
Intracellular Signaling Peptides and Proteins
Ligands
Membrane Proteins
Peptides