Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

NEUROPHARMACOLOGY

卷:150

Article

Bach, Anders¹  Clausen, Bettina H.^2,3  Kristensen, Lotte K.^{4,12,13,14,15}  Andersen, Maria G.^2,16  Ellman, Ditte Gry²  Hansen, Pernille B. L.^5,17  Hasseldam, Henrik⁴  Heitz, Marc^1,18  Ozcelik, Dennis¹  Tuck, Ellie J.^6,19  Kopanitsa, Maksym V.^6,20  Grant, Seth G. N.⁷  Lykke-Hartmann, Karin^8,9,10  Johansen, Flemming F.⁴  Lambertsen, Kate L.^2,3,11  Stromgaard, Kristian¹ 

[1] Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark

[2] Univ Southern Denmark, Inst Mol Med, Dept Neurobiol Res, JB Winsloewsvej 21, DK-5000 Odense, Denmark

[3] Univ Southern Denmark, Dept Clin Res, BRIDGE, Brain Res,Interdisciplinary Guided Excellence, Odense, Denmark

[4] Univ Copenhagen, Copenhagen Bioctr, Mol Pathol Sect, BRIC, Copenhagen, Denmark

[5] Univ Southern Denmark, Inst Mol Med, Dept Cardiovasc & Renal Res, Odense, Denmark

[6] Synome Ltd, Babraham Res Campus, Cambridge, England

[7] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland

[8] Univ Aarhus, Dept Biomed, Aarhus, Denmark

[9] Univ Aarhus, Dept Clin Med, Aarhus, Denmark

[10] Aarhus Univ Hosp, Dept Clin Genet, Aarhus, Denmark

[11] Odense Univ Hosp, Dept Neurol, Odense, Denmark

[12] Minerva Imaging, Copenhagen, Denmark

[13] Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark

[14] Rigshosp, Cluster Mol Imaging, Dept Biomed Sci, Copenhagen, Denmark

[15] Univ Copenhagen, Copenhagen, Denmark

[16] ALK Abello AS, Horsholm, Denmark

[17] AstraZeneca, IMED Biotech Unit, Cardiovasc Renal & Metab, Gothenburg, Sweden

[18] Univ Bern, Dept Chem & Biochem, Bern, Switzerland

[19] Univ Cambridge, Gurdon Inst, Cambridge, England

[20] Imperial Coll, UK Dementia Res Inst, London, England

关键词: Dimeric inhibitor;    Ischemic stroke;    MAGUKs;    Neuroprotection;    PSD-95;   

DOI  :  10.1016/j.neuropharm.2019.02.035

来源: Elsevier

【 摘 要 】

Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-D-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.

【 授权许可】

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