uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Show others and affiliations
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 20, 6450-9 p.Article in journal (Refereed) Published
Abstract [en]

The protein-protein interaction between the NMDA receptor and its intracellular scaffolding protein, PSD-95, is a potential target for treatment of ischemic brain diseases. An undecapeptide corresponding to the C-terminal of the NMDA was used as a template for finding lead candidates for the inhibition of the PSD-95/NMDA receptor interaction. Initially, truncation and alanine scan studies were carried out, which resulted in a pentapeptide with wild-type affinity, as examined in a fluorescence polarization assay. Further examination was performed by systematic substitutions with natural and unnatural amino acids, which disclosed a tripeptide with micromolar affinity and N-methylated tetrapeptides with improved affinities. Molecular modeling studies guided further N-terminal modifications and introduction of a range of N-terminal substitutions dramatically improved affinity. The best compound, N-cyclohexylethyl-ETAV (56), demonstrated up to 19-fold lower K i value ( K i = 0.94 and 0.45 microM against PDZ1 and PDZ2 of PSD-95, respectively) compared to wild-type values, providing the most potent inhibitors of this interaction reported so far. These novel and potent inhibitors provide an important basis for development of small molecule inhibitors of the PSD-95/NMDA receptor interaction.

Place, publisher, year, edition, pages
2008. Vol. 51, no 20, 6450-9 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-89319DOI: 10.1021/jm800836wISI: 000260102700021PubMedID: 18811137OAI: oai:DiVA.org:uu-89319DiVA: diva2:160088
Available from: 2009-02-11 Created: 2009-02-11 Last updated: 2011-06-28Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Jemth, Per
By organisation
Department of Medical Biochemistry and Microbiology
In the same journal
Journal of Medicinal Chemistry
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 288 hits
ReferencesLink to record
Permanent link

Direct link