Compound for inhibition of certain signaling processes related to the evolution of the cognitive processes

Compound for inhibition of certain signaling processes related to the evolution of the cognitive processes 2017-2018
Acronym: Ctr.327/27.03.2017/Company CRU SRL, Medical Services Company/ Dunakesz, Hungary
Project director: Stefan Szedlacsek
External website: full link

The main idea of this project was that by inhibiting at least one of these two interactions of GluA2, the internalization of AMPAR will be reduced and therefore the synapse resistance will be increased, thus leading to improved cognitive functions.

Compound for inhibition of certain signaling processes related to the evolution of the cognitive processes

Initiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization requires the interaction of the C-terminus of GluA2 with two proteins:

  1. With STEP to dephosphorylate Tyr876 and
  2. With BRAG2 to activate the small GTPase Arf6. 

The main idea of this project was that by inhibiting at least one of these two interactions of GluA2, the internalization of AMPAR will be reduced and therefore the synapse resistance will be increased, thus leading to improved cognitive functions.

Stefan Szedlacsek, Dr.
Stefan Szedlacsek, Dr.

Head of Department

Professor Dr. Stefan Eugen Szedlacsek is the Head of the Enzymology Department at the Institute of Biochemistry of the Romanian Academy. He holds a PhD degree in Biotechnology from Polytechnic University of Bucharest as well as a MSc in Organic Synthesis (Polytechnic University- Bucharest) and MSc in Mathematics (Bucharest University). As a visiting scientist, he performed research in the field of cholesterol metabolism University of Illinois at Urbana-Champaign (USA), where he succeeded to evidence a new pathway in the metabolism of oxysterols. He is an “Alexander von Humboldt“ fellow and worked in Germany, in the Institute of Biochemistry (Kiel University) More...

Andreea Pop
Andreea Pop

PhD Student

Bica Constantin Catalin, MSc
Bica Constantin Catalin, MSc

Asistent

Bica Constantin Catalin is a researcher in the Institute of Biochemistry of the Romanian Academy. Bica is currently working in Enzymology in the Enzymology.

Horea Szedlacsek
Horea Szedlacsek

Research Assistant

Horea Szedlacsek is a researcher in the Institute of Biochemistry of the Romanian Academy. Horea is currently working in Enzymology in the Enzymology.

Rodica-Aura Badea, Dr.
Rodica-Aura Badea, Dr.

Scientific Researcher

Rodica-Aura Badea is a researcher in the Institute of Biochemistry of the Romanian Academy. Rodica-Aura is currently working in Cell Signaling Research in the Enzymology.

CRU Hungary Kft Göd, Hungary

Lilla Ravasz, PhD Student

Dániel Mittl, PhD Student

Dominik Mátyás, PhD Student

Ildikó Papp, Dr.

Gábor Juhász,Dr,

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary

Dávid Bajusz, PhD Student

György Miklós Keserű, Dr.

Alexandru Ioan Cuza University, Iași, Romania

Lucian Hrițcu, Dr.

Generation of 2-3 peptides with the potential to improve cognitive functions

Highly effective inhibitors of AMPAR internalization were identified using 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 represent promising lead compounds for novel cognitive enhancers and/or behavioral modulators.

Poster presentation at the 37th Annual Protein Society Symposium at Boston (USA): „Rationally Designed Peptides Improve Cognition in Rats”, HS. Szedlacsek; D. Bajusz; RA. Badea; A. Pop; CC. Bică; L. Ravasz; D. Mittli; D. Mátyás; G. Necula-Petrăreanu; CV. Munteanu; I. Papp; G. Juhász; L. Hritcu; K. György; ȘE. Szedlacsek; July 13-16, 2023

Published papers: Designed Peptide Inhibitors of STEP Phosphatase-GluA2 AMPA Receptor Interaction Enhance the Cognitive Performance in Rats”: Szedlacsek HS, Bajusz D, Badea RA, Pop A, Bică CC, Ravasz L, Mittli D, Mátyás D, Necula-Petrăreanu G, Munteanu CVA, Papp I, Juhász G, Hritcu L, Keserű GM, Szedlacsek SE, https://pubmed.ncbi.nlm.nih.gov/34962802/, https://doi.org/10.1021/acs.jmedchem.1c01303; Published online: 28 December 2021; Published in issue: 13 January 2022; IF = 7,45

Invited lectures/speaker

  1. Oral lecture on “Designed Peptide Inhibitors of STEP Phosphatase-GluA2 AMPA Receptor Interaction Enhance the Cognitive Performance in Rats”, University of Debrecen, Hungary, May 17 2023.
  2. Online oral lecture in the Laboratory of Clinical Cognitive Sciences on "Nootropic peptides and memory: Implications for Alzheimer's prevention" Bucharest, Romania, March 17 2023.
  3. Invited speaker within a Fulbright Visiting Scholar Program at Seton Hall University, Department of Chemistry and Biochemistry, South Orange, New Jersey (USA); Oral presentation: „Rationally Designed Peptides Improve Cognition in Rats”; 22-26 January 2023
  4. Invited speaker within a Fulbright Visiting Scholar Program for the Chemistry Seminar Series at Clarkson University, NY (USA); "Applications of synthetic biology: rationally designed peptides and affibodies for biomedical applications"; 20-21 January 2023
  5. Oral lecture on "New results in the field of STEP inhibitors and synaptic enlargement"; Proteomics Laboratory of the Institute of Biology at Eötvös Loránd University in Budapest, Hungary; 07-09 September 2016;