2. Academic Validation
  3. Designed Peptide Inhibitors of STEP Phosphatase-GluA2 AMPA Receptor Interaction Enhance the Cognitive Performance in Rats

Designed Peptide Inhibitors of STEP Phosphatase-GluA2 AMPA Receptor Interaction Enhance the Cognitive Performance in Rats

  • J Med Chem. 2022 Jan 13;65(1):217-233. doi: 10.1021/acs.jmedchem.1c01303.
Horea Stefan Szedlacsek 1,  Dávid Bajusz 2,  Rodica Aura Badea 1,  Andreea Pop 1,  Constantin Cătălin Bică 1,  Lilla Ravasz 3,  Dániel Mittli 3,  Dominik Mátyás 3,  Georgiana Necula-Petrăreanu 1,  Cristian V A Munteanu 4,  Ildikó Papp 3,  Gábor Juhász 3,  Lucian Hritcu 5,  György Miklós Keserű 2,  Stefan Eugen Szedlacsek 1
Affiliations

Affiliations

  • 1 Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, 060031 Bucharest, Romania.
  • 2 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
  • 3 CRU Hungary Kft, Thököly utca 15, 2131 Göd, Hungary.
  • 4 Department of Bioinformatics and Structural Biochemistry, Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296, 060031 Bucharest, Romania.
  • 5 Department of Biology, Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700505 Iasi, Romania.
PMID: 34962802 DOI: 10.1021/acs.jmedchem.1c01303
Abstract

Cognitive impairment and learning ability of the brain are directly linked to synaptic plasticity as measured in changes of long-term potentiation (LTP) and long-term depression (LTD) in animal models of brain diseases. LTD reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. AMPA receptor endocytosis is initiated by dephosphorylation of Tyr876 on the C-terminus of the AMPAR subunit GluA2. The brain-specific striatal-enriched protein tyrosine Phosphatase (STEP) is responsible for this process. To identify new, highly effective inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization, we performed structure-based design of Peptides able to inhibit STEP-GluA2-CT complex formation. Two short peptide derivatives were found as efficient in vitro inhibitors. Our in vivo experiments evidenced that both Peptides restore the memory deficits and display anxiolytic and antidepressant effects in a scopolamine-treated rat model. The interference Peptides identified and characterized here represent promising lead compounds for novel cognitive enhancers and/or behavioral modulators.

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