MIPT: Prototype Gluten Intolerance Drug

The main articles are:

• Gluten
• Celiac disease

2024: Developing a Prototype Gluten Intolerance Drug

MIPT has developed a prototype medicine for gluten intolerance. It was possible to create a 3D model of the future drug substance using the AlphaFold neural network. The main active substance was the enzyme transglutaminase (tTG). Study findings published in journal Scientific Reports. This was announced on September 13, 2024 by representatives of the Moscow Institute of Physics and Technology.

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Scientific Reports

As reported, celiac disease - as of September 2024, one of the most common chronic diseases of the digestive system. According to WHO, approximately 1% of the world's population (about 75 million people) suffers from gluten intolerance. In the course of research, MIPT employees managed to obtain a complete 3D model of the atomic resolution of tissue transglutaminase (tTG), an enzyme that plays a leading role in the occurrence of celiac disease. In addition, with the help of computer screening, they created a library of potential inhibitors (blockers) of this enzyme.

The object of our study was not chosen by chance. Celiac disease is a fairly common disease. According to statistics for 2024, it is found in about every 100th person on the planet. One of the co-authors of the article, Vladimir Ivashchenko, is a carrier of this disease. shared Sergey Ivashchenko, engineer of the Laboratory of Molecular and Cell Biology and Optogenetics of MIPT

Tissue transglutaminase (tTG) can exist in two forms - "open" and "closed," depending on external conditions. It is the "open" form that participates in the modification of gluten peptides, which leads to inflammation. As of September 2024, drugs are available on the market that only indirectly affect the activity of tTG, while specific inhibitors have not yet been widely used.

Irreversible peptidomimetic tTG inhibitors are considered promising drug prototypes. One such drug, ZED1227, has undergone phase 2a clinical trials for the treatment of celiac disease, demonstrating its safety and confirming the feasibility of using tTG as a drug target.

Modern methods of drug development often include the stage of computer (in silico) analysis - high-performance docking, for which the quality of the three-dimensional structure of the target under study plays a decisive role. Scientists from MIPT were able to predict using the AlphaFold neural network a complete 3D model of tTG in an open conformation, which was confirmed by the results of molecular docking and modeling of molecular dynamics. The resulting structure not only clarifies the position of the amino acid residues critical for enzyme activity, but also describes the previously unknown position of the residues near the active site.

Previous tTG structures were only partially resolved (i.e. contained "voids," including in the active site of the enzyme), which did not allow the correct use of computer modeling methods. Our structure is the first complete tTG model that contains an additional loop that has an impact on ligand binding efficiency. explained by Sergey Ivashchenko

Based on the created enzyme model, the scientists collected a library of potential tTG inhibitors proposed for further experimental testing. These small molecule compounds, most of which have not been previously known, show a higher affinity for tTG in silico compared to those already known. Among the compounds found, 12 Bemis-Murcoe scaffolds (molecular scaffolds) were isolated, one of which corresponds to peptidomimetics, and the other three scaffolds showed the best binding results to the target. Due to its greater bioavailability, small molecules can become an alternative to tTG inhibitor peptidomimetics.

Thus, the results obtained are important both for basic research related to the study of structural-dynamic features of tTG and for applied purposes, significantly expanding the range of compounds with the potential for treating diseases associated with tTG. The work was carried out jointly by scientists from MIPT,, and Lomonosov Moscow State University FSBEI HE ROSBIOTECH () JINR Dubna with financial support. Ministries of Science and Higher Education of the Russian Federation