2. Academic Validation
  3. Engineering Peptide Modulators for T-Cell Migration by Structural Scaffold Matching

Engineering Peptide Modulators for T-Cell Migration by Structural Scaffold Matching

  • J Med Chem. 2025 Aug 28;68(16):17202-17220. doi: 10.1021/acs.jmedchem.5c00677.
Jasmin Gattringer 1,  Simon Hasinger 1,  Agnes Weidmann 1,  Katarzyna Walczewska-Szewc 2,  Kirtikumar B Jadhav 3,  Tobias Zrzavy 4 5,  Anja Steinmaurer 4 5,  Paulien Baeten 6,  Monika Perisic 3 7,  Wilson Cochrane 8,  Markus Muttenthaler 3 9,  Bieke Broux 6,  Dagmar Gotthardt 10,  K Johan Rosengren 8,  Christian W Gruber 1,  Roland Hellinger 1
Affiliations

Affiliations

  • 1 Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
  • 2 Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland.
  • 3 Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, 1090 Vienna, Austria.
  • 4 Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Vienna, Austria.
  • 5 Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
  • 6 Department of Immunology and Infection Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium.
  • 7 Vienna Doctoral School in Chemistry, University of Vienna, 1090 Vienna, Austria.
  • 8 School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 9 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 10 Department for Biological Sciences and Pathobiology, Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
PMID: 40795266 DOI: 10.1021/acs.jmedchem.5c00677
Abstract

Lymphocyte migration plays a crucial role in the progression of autoimmune and inflammatory diseases, and the inhibition of autoreactive immune cells is an attractive therapeutic strategy. Pepitem is an endogenous modulator of lymphocyte migration. In this study, we implemented a structural scaffold matching approach to engineer of stabilized pepitem-based probes. Prioritizing the native helix-loop-helix structure of pepitem, protein structure databases were mined to identify the structurally closest peptide scaffold. Leveraging this strategy, we developed VhTI-pep 2, inhibiting CD3+ T-lymphocyte migration in vitro with a comparable potency (EC50 = 10.6 ± 16.5 nM) to pepitem (EC50 = 6.0 ± 6.4 nM). Its potency was further extended to T-cell subsets derived from multiple sclerosis patients and highly disease-driving memory and Th1 cell populations. Our approach will guide the design of stabilized peptide probes and future therapeutics, overcoming the challenges associated with flexible and linear peptides.

Figures
Products