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

Anders* Bach; Bettina H Clausen; Magda Møller; Bente Vestergaard; Celestine N Chi; Adam Round; Pernille Louise Sørensen; Klaus Bertram Nissen; Jette Sandholm Kastrup; Michael Gajhede; Per Jemth; Anders Skov Kristensen; Patrik Lundström; Kate Lykke Lambertsen; Kristian* (*Corresponding) Strømgaard

doi:10.1073/pnas.1113761109

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

Anders* Bach, Bettina H Clausen, Magda Møller, Bente Vestergaard, Celestine N Chi, Adam Round, Pernille Louise Sørensen, Klaus Bertram Nissen, Jette Sandholm Kastrup, Michael Gajhede, Per Jemth, Anders Skov Kristensen, Patrik Lundström, Kate Lykke Lambertsen, Kristian* (*Corresponding) Strømgaard

118 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Proceedings of the National Academy of Sciences of the United States of America
Vol/bind	109
Udgave nummer	9
Sider (fra-til)	3317-3322
ISSN	0027-8424
DOI	https://doi.org/10.1073/pnas.1113761109
Status	Udgivet - 28 feb. 2012

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10.1073/pnas.1113761109

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Bach, A., Clausen, B. H., Møller, M., Vestergaard, B., Chi, C. N., Round, A., Sørensen, P. L., Nissen, K. B., Kastrup, J. S., Gajhede, M., Jemth, P., Kristensen, A. S., Lundström, P., Lambertsen, K. L., & 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

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 et al.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 109, Nr. 9, 28.02.2012, s. 3317-3322.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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, bind 109, nr. 9, s. 3317-3322. https://doi.org/10.1073/pnas.1113761109

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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",

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doi = "10.1073/pnas.1113761109",

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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

SN - 0027-8424

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

IS - 9

ER -

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

Abstract

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