Design of azidoproline containing gluten peptides to suppress CD4+ T-cell responses associated with Celiac disease

Kapoerchan, Varsha V.; Wiesner, Martina; Overhand, Mark; Marel, Gijs A. van der; Koning, Frits; Overkleeft, Herman S.

doi:10.1016/j.bmc.2007.10.091

Cited by 58 publications

(25 citation statements)

References 15 publications

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“…[77] Humans suffering from Celiac disease have specific HLA alleles that bind certain gluten peptides, triggering an undesired immune response. The researchers explored the possibility of designing peptides that, once bound to the implicated HLA alleles, would prevent T-cells from recognising the HLA-peptide complex, thus silencing the adverse immune response.…”

Section: Side Chain Modificationsmentioning

confidence: 99%

1,2,3‐Triazoles in Peptidomimetic Chemistry

2011

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The ability to synthesise small peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small peptidomimetics that are easy to prepare. The copper‐ and ruthenium‐catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3‐triazoles being good peptide bond mimics. The ability to prepare both 1,4‐ and 1,5‐substituted 1,2,3‐triazoles under these chemically benign conditions provides both “linear” and “bent” peptidomimetics. Examples of the use of 1,2,3‐triazoles to define the geometry and properties of a peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area.

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Section: Side Chain Modificationsmentioning

confidence: 99%

1,2,3‐Triazoles in Peptidomimetic Chemistry

2011

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“…So far, the most promising approaches for blocking of the HLA-DQ2.5 mediated presentation of gluten derived antigens is the use of cyclic and dimeric gluten peptides, 7 or the introduction of a large, chemically modified side chain into gluten epitopes. 8 However, the efficacy of the designed blockers for inhibiting T cell activation in vitro is inadequate, and it appears that insufficient affinity of the blockers for HLA-DQ2.5 is at least one limitation.…”

Section: Introductionmentioning

confidence: 99%

Assessing high affinity binding to HLA-DQ2.5 by a novel peptide library based approach

Jüse

Arntzen

Højrup

et al. 2011

Bioorganic & Medicinal Chemistry

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“…Pharmaceutical scientists face interesting challenges in overcoming shortcomings with potentially negative effects on compliance and therapeutic benefit (in red). (60) in the stomach and the small intestine) (37). The binding of the polymer to important nutrients has been pointed out as a potential drawback of this approach.…”

Section: Polymeric Bindersmentioning

confidence: 99%

“…TG2-inhibitors might prove more useful in combination therapy since some gluten peptides are immunogenic without TG2-mediated deamidation (59). Another approach consists in blocking HLA-DQ2 and DQ8 with high avidity peptidic ligands in order to inhibit the presentation of immunogenic gluten-derived peptides by APCs (60). Challenging aspects of the HLA-blocking approach are the peptidic nature of the competitive HLA-blockers, which makes them prone to degradation in the GI tract, the need for high concentration and avidity, as well as possible interference with presentation of peptides from pathogens on HLA-DQ2 and DQ8 (8).…”

Section: Tg2-inhibitors and Hla-blockersmentioning

confidence: 99%

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

2012

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Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains that affects~1% of the white ethnic population. In the last decades, a rise in prevalence of CD has been observed that cannot be fully explained by improved diagnostics. Genetic predisposition greatly influences the susceptibility of individuals towards CD, though environmental factors also play a role. With no pharmacological treatments available, the only option to keep CD in remission is a strict and permanent exclusion of dietary gluten. Such a gluten-free diet is difficult to maintain because of gluten's omnipresence in food (e.g., additive in processed food). The development of adjuvant therapies which would permit the intake of small amounts of gluten would be desirable to improve the quality of life of patients on a glutenfree diet. Such therapies include gluten-degrading enzymes, polymeric binders, desensitizing vaccines, anti-inflammatory drugs, transglutaminase 2 inhibitors, and HLA-DQ2 blockers. However, many of these approaches pose pharmaceutical challenges with respect to drug formulation and stability, or application route and dosing interval. This perspective article discusses how pharmaceutical scientists may deal with these challenges and contribute to the implementation of novel therapeutic options for patients with CD.

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Design of azidoproline containing gluten peptides to suppress CD4+ T-cell responses associated with Celiac disease

Cited by 58 publications

References 15 publications

1,2,3‐Triazoles in Peptidomimetic Chemistry

1,2,3‐Triazoles in Peptidomimetic Chemistry

Assessing high affinity binding to HLA-DQ2.5 by a novel peptide library based approach

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

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