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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.
Vise andre og tillknytning
2012 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, nr 9, s. 3317-3322Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
National Academy of Sciences , 2012. Vol. 109, nr 9, s. 3317-3322
Emneord [en]
drug discovery, ischemic stroke, protein-protein interactions
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-75899DOI: 10.1073/pnas.1113761109ISI: 000300828200031OAI: oai:DiVA.org:liu-75899DiVA, id: diva2:510551
Merknad
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|Tilgjengelig fra: 2012-03-16 Laget: 2012-03-16 Sist oppdatert: 2017-12-07

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