Developing New Mode-of-Action Calcineurin Inhibitors for Acute Colitis Therapeutics

Targeting the calcineurin-NFAT protein-protein interaction rather than enzyme active sites, this project develops a novel class of inhibitors to treat steroid-refractory ulcerative colitis with fewer side effects.
Ongoing Gastrointestinal Diseases Ulcerative Colitis Biological & Mechanistic Cytokine Signaling Experimental Platforms & Models In Vitro Models T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Acute severe ulcerative colitis is an autoimmune disease with limited treatment options. Current calcineurin inhibitors such as cyclosporine carry significant toxicity and are suitable only for short-term use, leaving many patients without a path to sustained remission. This project develops a new class of inhibitors that block the interaction between calcineurin and NFAT — two proteins central to immune activation and disease progression — rather than targeting enzyme catalytic sites. A large compound library screen identified several promising peptide candidates, which are now being characterized and optimized. Each molecule represents a new chemical entity, with composition-of-matter patent protection anticipated, and a clear path toward clinical development following in vitro and in vivo validation.

Impact & Innovation

A new mechanism for an old therapeutic target.

 

By blocking the calcineurin-NFAT protein-protein interaction rather than enzyme active sites, this project introduces a fundamentally more precise class of calcineurin inhibitors — with fewer off-target effects and a clear path to clinical development in steroid-refractory colitis.

  • Introduces protein-protein interaction inhibition as a novel mode of action for calcineurin blockade, offering greater specificity than classic small-molecule enzyme inhibitors with reduced toxicity potential
  • Generates IP potential through novel chemical entities eligible for composition-of-matter patent protection, building a strong foundation for commercialization
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving peptide candidates from library screen through in vitro and in vivo characterization toward clinical development for steroid-refractory acute severe ulcerative colitis
Research Approach

Methods, sources, and focus

This project combines peptide chemistry, protein interaction biology, and preclinical disease modeling to characterize and optimize calcineurin-NFAT inhibitors identified through a large-scale compound library screen. The work moves from hit characterization and molecular refinement through in vitro and in vivo validation toward therapeutic development.

Experimental or Computational Methods (High-Level): Characterization and optimization of peptide candidates identified from a large compound library screen targeting the calcineurin-NFAT protein-protein interaction, followed by in vitro functional assays to assess potency and selectivity, and in vivo testing in colitis models to evaluate therapeutic efficacy and safety.

Data Sources or Models Used: Large peptide compound library screen data, in vitro cell-based assays measuring calcineurin-NFAT interaction inhibition and immune activation, and in vivo mouse models of acute colitis for preclinical efficacy and tolerability assessment.

Optimization of lead peptide candidates into refined therapeutics with improved potency, selectivity, and safety profiles relative to existing calcineurin inhibitors. Successful candidates are intended to advance into clinical development as a new class of treatments for steroid-refractory acute severe ulcerative colitis.

Investigators & Institutions

Powering the Science

Principal Investigators

Maayan Gal, PhD, Colton Consortium Member

Associate Professor, Structural Biology, Tel Aviv University

Ehud Zigmond, MD, PhD, Colton Consortium Member

Director of the Liver Diseases Center, Gastroenterology, Sheba Medical Center, Tel Aviv University

Colton Centers & Institutions

Colton Center for Autoimmunity at Tel Aviv University

School of Dental Medicine, Tel Aviv University

The Center of Liver Disease, Sheba Medical Center