high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
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 lac...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 9; pp. 3317 - 3322 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
28.02.2012
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Edited by James A. Wells, University of California, San Francisco, San Francisco, CA, and approved January 4, 2012 (received for review August 23, 2011) Author contributions: A.B., B.H.C., B.V., C.N.C., M.G., P.J., A.S.K., K.L.L., and K.S. designed research; A.B., B.H.C., M.M., C.N.C., A.R., P.L.S., K.B.N., P.L., and K.L.L. performed research; A.B., B.H.C., B.V., C.N.C., J.S.K., M.G., P.L., K.L.L., and K.S. analyzed data; and A.B. and K.S. wrote the paper. |
ISSN: | 0027-8424 1091-6490 1091-6490 |
DOI: | 10.1073/pnas.1113761109 |