Celiac Disease (CD) is an inheritable autoimmune disease characterized by a severe immune response to gluten protein. This disease targets 7 in 1000 people worldwide [1] and requires a patient to have a lifelong gluten-free diet, which remains the sole viable option for therapy and mitigation of the symptoms. Some strategies to combat the disease utilize negatively charged antigen nanoparticles, vaccines, monoclonal IL-15 antibodies, endopeptidases, and gluten sequestration [2]. However, one of the most feasible options remains slight molecule inhibition of proteins that partake in proinflammatory immune reaction cascade or regulate tight junction, namely JAK, MLCK, and ROC Kinases [3–5], as well as Transglutaminase 2 [6].
To satisfy the need for selective prominent drug targets, Life Chemicals is proud to contribute to celiac disease treatment research with its new Celiac Disease Screening Library of over 1,200 drug-like screening compounds. These molecules have been shown to target protein-glutamine gamma-glutamyltransferase 2 (TG2), responsible for the enzymatic modification of gliadin peptides, a key mechanism in the pathogenesis of celiac disease [7]. The process is illustrated schematically in Figure 1.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure1. Celiac disease pathophysiological mechanism in the intestine.
Notes: Ingested gluten is broken into peptides by human endopeptidases. Gluten peptides are deaminated by Transglutaminase II (TG2) presented by APC to CD4+ T-cells that secrete pro-inflammatory cytokines and promote activation of intraepithelial T lymphocytes that initiate destruction of enterocytes. IL-15 interferes with T-cells' suppressive mechanism, which causes immune response dysregulation.
Compound selection
This Screening Library consists of more than 1,200 small-molecule screening compounds divided into two subsets based on the selection method.
The first subset was created by obtaining activity data from the ChEMBL database with high experimental activity against TGM2. A subsequent two-dimensional fingerprint similarity search was performed against the HTS Compound Collection using a Tanimoto index threshold of ≥ 0.85 to result in the selection of 130 close analogs of TGM2 inhibitors.
The second subset was obtained by performing docking-based virtual screening using X-ray structural data of Transglutaminase 2 complexed with GTP (RCSB PDB ID: 4PYG) according to additional physiological barrier permeability assessment. It resulted in over 1,100 potential modifiers of human TG2. Respective values for docking score, barrier permeability, and RO3 and RO5 compliance are available in the compound structure file.
Representative screening compounds from the Screening Library
Reference:
- Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global prevalence of celiac disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16:823–3600.
- (Caio, Giacomo et al. “Celiac disease: a comprehensive current review.” BMC medicine vol. 17,1 142. 23 Jul. 2019, doi:10.1186/s12916-019-1380-z.
- Losso J., Food Processing, Dysbiosis, Gastrointestinal Inflammatory Diseases, and Antiangiogenic Functional Foods or Beverages, ANNUAL REVIEW OF FOOD SCIENCE AND TECHNOLOGY, Vol. 12:235-258, Jan 2021. DOI:10.1146/annurev-food-062520-090235.
- Turner JR, Rill BK, Carlson SL, et al. Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am J Physiol. 1997;273:C1378–C1385.
- Walsh SV, Hopkins AM, Chen J, Narumiya S, Parkos CA, Nusrat A. Rho kinase regulates tight junction function and is necessary for tight junction assembly in polarized intestinal epithelia. Gastroenterology. 2001;121:566–579.
- Rauhavirta, Tiina et al. “Transglutaminase 2 and Transglutaminase 2 Autoantibodies in Celiac Disease: a Review.” Clinical reviews in allergy & immunology vol. 57,1 (2019): 23-38. doi:10.1007/s12016-016-8557-4.
- Stricker S, de Laffolie J, Zimmer K-P, Rudloff S. Inhibition of Transglutaminase 2 as a Therapeutic Strategy in Celiac Disease—In Vitro Studies in Intestinal Cells and Duodenal Biopsies. International Journal of Molecular Sciences. 2023; 24(5):4795. https://doi.org/10.3390/ijms24054795.