A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain.

Autor: Christensen NR; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., De Luca M; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Lever MB; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Richner M; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Hansen AB; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Noes-Holt G; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jensen KL; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Rathje M; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jensen DB; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Erlendsson S; Structural biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Bartling CR; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Ammendrup-Johnsen I; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Pedersen SE; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Schönauer M; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Nissen KB; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Midtgaard SR; Structural Biophysics, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark., Teilum K; Structural biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Arleth L; Structural Biophysics, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark., Sørensen AT; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Bach A; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Strømgaard K; Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, Copenhagen, Denmark., Meehan CF; Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Vaegter CB; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic-EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Aarhus C, Denmark., Gether U; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Madsen KL; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2020 Jun 08; Vol. 12 (6), pp. e11248. Date of Electronic Publication: 2020 Apr 30.
DOI: 10.15252/emmm.201911248
Abstrakt: Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P 4 -(C5) 2 , of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat-P 4 -(C5) 2 disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA-receptor surface expression in vivo. Moreover, Tat-P 4 -(C5) 2 administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat-P 4 -(C5) 2 as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non-tandem protein-protein interaction domains.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
Externí odkaz: