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

Research output: Contribution to journalJournal articleResearchpeer-review

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A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. / Bach, Anders*; Clausen, Bettina H; Møller, Magda; Vestergaard, Bente; Chi, Celestine N; Round, Adam; Sørensen, Pernille Louise; Nissen, Klaus Bertram; Kastrup, Jette Sandholm; Gajhede, Michael; Jemth, Per; Kristensen, Anders Skov; Lundström, Patrik; Lambertsen, Kate Lykke; Strømgaard, Kristian* (*Corresponding).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 9, 28.02.2012, p. 3317-3322.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Bach, A, Clausen, BH, Møller, M, Vestergaard, B, Chi, CN, Round, A, Sørensen, PL, Nissen, KB, Kastrup, JS, Gajhede, M, Jemth, P, Kristensen, AS, Lundström, P, Lambertsen, KL & Strømgaard, KC 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, vol. 109, no. 9, pp. 3317-3322. https://doi.org/10.1073/pnas.1113761109

APA

Bach, A., Clausen, B. H., Møller, M., Vestergaard, B., Chi, C. N., Round, A., ... Strømgaard, K. C. (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

Vancouver

Bach A, Clausen BH, Møller M, Vestergaard B, Chi CN, Round A et al. 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. 2012 Feb 28;109(9):3317-3322. https://doi.org/10.1073/pnas.1113761109

Author

Bach, Anders* ; Clausen, Bettina H ; Møller, Magda ; Vestergaard, Bente ; Chi, Celestine N ; Round, Adam ; Sørensen, Pernille Louise ; Nissen, Klaus Bertram ; Kastrup, Jette Sandholm ; Gajhede, Michael ; Jemth, Per ; Kristensen, Anders Skov ; Lundström, Patrik ; Lambertsen, Kate Lykke ; Strømgaard, Kristian* (*Corresponding). / A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 9. pp. 3317-3322.

Bibtex

@article{e7bef3927d2b49dea76046154795bb3c,
title = "A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage",
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.",
author = "Anders* Bach and Clausen, {Bettina H} and Magda M{\o}ller and Bente Vestergaard and Chi, {Celestine N} and Adam Round and S{\o}rensen, {Pernille Louise} and Nissen, {Klaus Bertram} and Kastrup, {Jette Sandholm} and Michael Gajhede and Per Jemth and Kristensen, {Anders Skov} and Patrik Lundstr{\"o}m and Lambertsen, {Kate Lykke} and Str{\o}mgaard, {Kristian* (*Corresponding)}",
note = "Keywords: drug discovery; ischemic stroke; protein-protein interactions",
year = "2012",
month = "2",
day = "28",
doi = "10.1073/pnas.1113761109",
language = "English",
volume = "109",
pages = "3317--3322",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "9",

}

RIS

TY - JOUR

T1 - A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage

AU - Bach, Anders

AU - Clausen, Bettina H

AU - Møller, Magda

AU - Vestergaard, Bente

AU - Chi, Celestine N

AU - Round, Adam

AU - Sørensen, Pernille Louise

AU - Nissen, Klaus Bertram

AU - Kastrup, Jette Sandholm

AU - Gajhede, Michael

AU - Jemth, Per

AU - Kristensen, Anders Skov

AU - Lundström, Patrik

AU - Lambertsen, Kate Lykke

AU - Strømgaard, Kristian (Corresponding)

N1 - Keywords: drug discovery; ischemic stroke; protein-protein interactions

PY - 2012/2/28

Y1 - 2012/2/28

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1113761109

DO - 10.1073/pnas.1113761109

M3 - Journal article

C2 - 22343531

VL - 109

SP - 3317

EP - 3322

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -

ID: 37796948