A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage

A. Bach, B. H. Clausen, M. Moller, B. Vestergaard, C. N. Chi, A. Round, P. L. Sorensen, K. B. Nissen, J. S. Kastrup, M. Gajhede, P. Jemth, A. S. Kristensen, P. Lundstrom, K. L. Lambertsen, K. Stromgaard

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Abstract

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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number9
Pages (from-to)3317-3322
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 2012

Cite this

Bach, A., Clausen, B. H., Moller, M., Vestergaard, B., Chi, C. N., Round, A., Sorensen, P. L., Nissen, K. B., Kastrup, J. S., Gajhede, M., Jemth, P., Kristensen, A. S., Lundstrom, P., Lambertsen, K. L., & Stromgaard, K. (2012). A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proceedings of the National Academy of Sciences of the United States of America, 109(9), 3317-3322. https://doi.org/10.1073/pnas.1113761109