liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
University of Copenhagen.
University of South Denmark.
University of Copenhagen.
University of Copenhagen.
Show others and affiliations
2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 9, 3317-3322 p.Article in journal (Refereed) Published
Abstract [en]

Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 9, 3317-3322 p.
Keyword [en]
drug discovery, ischemic stroke, protein-protein interactions
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-75899DOI: 10.1073/pnas.1113761109ISI: 000300828200031OAI: diva2:510551
Funding Agencies|Danish Council for Independent Research||Lundbeck Foundation||GluTarget||Swedish Research Council|2009-56592008-4285|Novo Nordisk Foundation||Carlsberg Foundation||Danish Council for Strategic Research||Programme Commission on Nanoscience, Biotechnology and Information and Communication Technology (NABIIT)|09-060780|Available from: 2012-03-16 Created: 2012-03-16 Last updated: 2012-04-03

Open Access in DiVA

fulltext(1257 kB)813 downloads
File information
File name FULLTEXT01.pdfFile size 1257 kBChecksum SHA-512
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Search in DiVA

By author/editor
Lundström, Patrik
By organisation
Molecular BiotechnologyThe Institute of Technology
In the same journal
Proceedings of the National Academy of Sciences of the United States of America
Engineering and Technology

Search outside of DiVA

GoogleGoogle Scholar
Total: 813 downloads
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: 41 hits
ReferencesLink to record
Permanent link

Direct link