Celiac disease, a chronic autoimmune disorder prevalent around 1 % globally and triggered by gluten ingestion, lacks effective pharmaceutical treatments beyond a lifelong adherence to a gluten-free diet [1-3]. At the same time, strict diet compliance is challenging due to the ubiquitous presence of gluten in many foods and the risk of accidental exposure. Moreover, some patients continue to experience symptoms (diarrhea, abdominal pain, malabsorption) and mucosal damage despite following a diet, a condition known as non-responsive celiac disease. Therefore, there is a significant unmet need for effective pharmacological therapies to supplement or replace the gluten-free diet and improve patients’ quality of life.
The pathogenesis of celiac disease (Fig. 1) involves an immune response to gluten-derived peptides, particularly gliadin [3-5]. These peptides are deamidated by tissue transglutaminase (tTG) in the gut, increasing their affinity for HLA-DQ2/DQ8 molecules on antigen-presenting cells. This interaction triggers an adaptive immune response, leading to the activation of gluten-specific T-cells and the release of pro-inflammatory cytokines, which cause intestinal damage. Key pathogenic pathways include increased intestinal permeability, which allows gluten peptides to cross the epithelial barrier and interact with immune cells, and the subsequent T-cell-mediated immune response. Understanding these pathways has led to the identification of potential therapeutic targets:
- Enzymes involved in gluten degradation: These enzymes can break down gluten peptides in the gastrointestinal tract before they trigger an immune response.
- Inflammatory cytokines and chemokines: Targeting these molecules can reduce inflammation and immune-mediated damage.
- Tight junction proteins: Modulating these proteins can enhance intestinal barrier function and prevent gluten peptide translocation.
Figure 1. Celiac disease pathophysiological mechanism in the intestine.
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.
Accordingly, recent drug discovery advancements focus on three main strategies: enzyme therapy, immunotherapy, and small molecule inhibitors [1,4,5]. Enzyme therapy aims at degrading gluten peptides into non-immunogenic fragments before they reach the small intestine. Examples include ALV003, a combination of two proteases that specifically target gluten. Clinical trials have demonstrated its ability to reduce gluten-induced mucosal damage in patients with celiac disease. Immunotherapy approach seeks to induce immune tolerance to gluten or modulate the immune response via designing immunotherapy vaccines, targeting pro-inflammatory cytokines with monoclonal antibodies, or reducing the immune response with gluten-specific T-cell modulators. Small molecule inhibitors include inhibitors of tTG, which prevent the deamidation of gluten peptides and reduce their immunogenicity by blocking the activity of tTG, and peptidase inhibitors, which inhibit enzymes that break down gluten into immunogenic peptides, thus preventing their formation.
Innovative screening technologies and preclinical research have significantly accelerated the discovery of potential therapeutic agents for celiac disease [7,8]. These innovations facilitate the identification and evaluation of novel compounds, providing a robust foundation for subsequent clinical development. For instance, the development of targeted screening libraries has sped up the identification of potential therapeutic compounds by enabling high-throughput screening of small molecules that may modulate celiac disease-related pathways.
The future of celiac disease treatment lies in harnessing emerging technologies and innovative approaches to develop more effective and personalized therapies. Ongoing research continues to uncover new insights into disease mechanisms, opening up promising avenues for novel therapeutic strategies. Emerging approaches in celiac disease treatment include personalized medicine based on genetic profiling, which could tailor therapies to individual patient characteristics. Combination therapies that target multiple pathogenic pathways simultaneously are also being explored to enhance treatment efficacy. Furthermore, advancements in drug discovery and a deeper understanding of celiac disease pathophysiology are expected to lead to significant breakthroughs in the next decade. The development of effective pharmacological therapies will likely transform celiac disease management, offering patients improved outcomes and quality of life.
To support the continued celiac disease treatment studies and collaboration in bringing new therapies to market, Life Chemicals has developed its Celiac Disease Screening Library of over 1,200 drug-like screening compounds (Fig. 2).
To diversify and expand the research toolbox, we also offer several related screening libraries:
Order your custom compound selections and enjoy the most convenient terms and competitive pricing.
Please, contact us at marketing@lifechemicals.com for any additional information and price quotations.
Download SD files with compound structures directly from our Downloads section
Figure 2. Representative screening compounds from the Life Chemistry Celiac Disease Screening Library
References
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Vaquero, L., Bernardo, D., León, F., Rodríguez-Martín, L., Alvarez-Cuenllas, B., & Vivas, S. (2019). Challenges to drug discovery for celiac disease and approaches to overcome them. Expert opinion on drug discovery, 14(10): 957-968. DOI: 10.1080/17460441.2019.1642321
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Plugis, N. M., & Khosla, C. (2015). Therapeutic approaches for celiac disease. Best practice & research Clinical gastroenterology, 29(3): 503-521. DOI: 10.1016/j.bpg.2015.04.005
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Sollid, L. M., & Khosla, C. (2011). Novel therapies for coeliac disease. Journal of internal medicine, 269(6): 604-613. DOI: 10.1111/j.1365-2796.2011.02376.x
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Asri, N., Rostami-Nejad, M., Rezaei-Tavirani, M., Razzaghi, M., Asadzadeh-Aghdaei, H., & Zali, M. R. (2020). Novel therapeutic strategies for celiac disease. Middle East journal of digestive diseases, 12(4): 229. DOI: 10.34172/mejdd.2020.187
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Dieckman, T., Koning, F., & Bouma, G. (2022). Celiac disease: New therapies on the horizon. Current opinion in pharmacology, 66: 102268. DOI: 10.1016/j.coph.2022.102268
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