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A high-affinity, di...
A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
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- Bach, Anders (author)
- University of Copenhagen
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- Clausen, Bettina H (author)
- University of South Denmark
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- Moller, Magda (author)
- University of Copenhagen
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- Vestergaard, Bente (author)
- University of Copenhagen
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- Chi, Celestine N. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala University
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- Round, Adam (author)
- European Molecular Biol Lab
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- Sorensen, Pernille L (author)
- University of Copenhagen
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- Nissen, Klaus B (author)
- University of Copenhagen
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- Kastrup, Jette S (author)
- University of Copenhagen
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- Gajhede, Michael (author)
- University of Copenhagen
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- Jemth, Per (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala University
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- Kristensen, Anders S (author)
- University of Copenhagen
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- Lundström, Patrik (author)
- Linköpings universitet,Molekylär Bioteknik,Tekniska högskolan
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- Lambertsen, Kate L (author)
- University of South Denmark
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- Stromgaard, Kristian (author)
- University of Copenhagen
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(creator_code:org_t)
- 2012-02-17
- 2012
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:9, s. 3317-3322
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Abstract
Subject headings
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- 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.
Keyword
- drug discovery
- ischemic stroke
- protein-protein interactions
- TECHNOLOGY
- TEKNIKVETENSKAP
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Bach, Anders
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Clausen, Bettina ...
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Moller, Magda
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Vestergaard, Ben ...
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Chi, Celestine N ...
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Round, Adam
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show more...
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Sorensen, Pernil ...
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Nissen, Klaus B
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Kastrup, Jette S
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Gajhede, Michael
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Jemth, Per
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Kristensen, Ande ...
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Lundström, Patri ...
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Lambertsen, Kate ...
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Stromgaard, Kris ...
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- Articles in the publication
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Proceedings of t ...
- By the university
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Linköping University
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Uppsala University