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Related Concept Videos

T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...

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Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
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Published on: January 26, 2016

AI-Designed Cyclic Peptides Enable Controllable Modulation of the CD28 Immune Checkpoint.

Katarzyna Kuncewicz1,2, Saurabh Upadhyay1, Renjie Zhu3

  • 1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|May 30, 2026
PubMed
Summary

AI-designed cyclic peptides offer controllable immune modulation by targeting CD28 checkpoints. This synthetic approach shows therapeutic potential for inflammatory diseases, unlike traditional biologics.

Keywords:
CD28cytokineimmune checkpointimmune systemimmunotherapyproinflammatory cytokine

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Area of Science:

  • Immunology
  • Synthetic Biology
  • Computational Drug Discovery

Background:

  • Immune checkpoint therapies, primarily biologics, face limitations in controllability and prolonged receptor occupancy.
  • Synthetic modalities targeting protein-protein interactions for immune modulation are underexplored.
  • The costimulatory receptor CD28 plays a crucial role in T-cell activation and immune responses.

Purpose of the Study:

  • To develop a novel, AI-guided strategy for discovering synthetic peptide antagonists of immune checkpoints.
  • To investigate the potential of cyclic peptides as controllable immunomodulatory agents.
  • To evaluate a lead cyclic peptide antagonist of CD28 for its therapeutic efficacy in preclinical models.

Main Methods:

  • Utilized an AI-guided strategy to identify cyclic peptide antagonists targeting the CD28 receptor.
  • Characterized the lead peptide (CIP-3) for binding affinity to CD28 and its ability to disrupt CD28-ligand interactions.
  • Assessed CIP-3's effects on CD28-dependent T-cell activation in human immune systems and its pharmacologic reversibility.
  • Evaluated CIP-3's therapeutic efficacy in a T-cell transfer model of chronic colitis and its impact on cytokine production in patient-derived cells.

Main Results:

  • Discovered CIP-3, a cyclic peptide antagonist of CD28 with nanomolar binding affinity.
  • Demonstrated that CIP-3 suppresses CD28-dependent T-cell activation without agonist activity and exhibits rapid, exposure-dependent reversibility.
  • Showed dose-dependent therapeutic efficacy of CIP-3 in a chronic colitis model, reducing inflammatory cytokines.
  • Confirmed CIP-3's ability to suppress cytokine production in healthy donors and ulcerative colitis patient PBMCs, comparable to anti-CD28 biologics.

Conclusions:

  • AI-designed cyclic peptides represent a promising controllable synthetic modality for immune checkpoint modulation.
  • CIP-3 offers a potential therapeutic strategy for immune-related diseases with enhanced pharmacologic control.
  • This approach advances the development of synthetic immunomodulatory agents beyond traditional biologics.