Projects / Programmes
New inhibitors of bacterial endotoxin receptor TLR4 based on binding to the hydrophobic pocket
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| T490 |
Technological sciences |
Biotechnology |
| B510 |
Biomedical sciences |
Infections |
MD-2, LPS, endotoxin, sepsis, ligand, innate immunity, inflammation response
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
17915 |
PhD Helena Gradišar |
Biotechnology |
Head |
2007 - 2008 |
130 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Abstract
The innate immune response enables the human body to recognize and rapidly respond to the bacterial infection. Excessive response to bacterial constituents, such as endotoxin (LPS) can lead to sepsis, where the medical treatment is usually symptomatic and mortality remains high. Activation of the immune cells is triggered by binding of LPS to the protein MD-2. MD-2 presents and important, yet little investigated target for the pharmacological inhibition of the LPS-induced inflammatory response. Compounds, which occupy the LPS-binding site on MD-2 represent leads for potential drugs against sepsis as well as against other diseases where the complex MD-2/TLR4 is involved (gastric carcinoma, rheumatoid arthritis, Crohn’s disease, atherosclerosis,..) In the proposed project, we will identify and evaluate MD-2 ligands, which bind to the LPS-binding site. In 3D model of MD-2, which we confirmed by mutants, we have located a free cysteine residue (Cys133) in the hydrophobic pocket of the protein. We anticipate that the compounds with affinity to this residue and with SH- reactive group will represent potent irreversible inhibitors of the inflammatory response. Candidates for the MD-2-binding ligands will be selected by the analysis of the literature data, with emphasis on the compounds with immunosupressive activity on LPS stimulation and by the structural analysis for either covalent or reversible type of inhibition. Among the candidates, substances of natural origin such as curcumin, catechins, resveratrol, capsaicin…, are particularly interesting due to their traditional use in the medicine. In case of curcumin, the reciprocal correlation between its dietary intake in form of spice turmeric (curry) and gastric carcinoma (Asian paradox), caused by the Gram-negative bacteria H. pylori indicates the possible inhibition of chronic inflammation because of the bacterial infection. Interaction of ligands with MD-2 and their use to inhibit LPS-signaling will be confirmed with direct-binging measurements as well as on cell culture experiments.
Significance for science
The results of the research project contribute to better understanding of inflammation disease molecular mechanisms where receptor complex TLR4/MD-2 is included. We established not well-investigated role of ligands which bind to MD-2 and inhibit the signaling pathway through the TLR4/MD-2 complex. We have shown that protein MD-2 with its hydrophobic pocket is a frequent target for the binding of compounds that are described as an immunosuppressive in the scientific publications. With an innovative approach in the selection of potential ligands, we identified new inhibitors which bind to the hydrophobic pocket of MD-2 and inhibit signaling through LPS-dependent pathway. The results of a new type inhibitor investigation were published in renowned scientific journals. The findings of the project are of medical and biotechnological importance. The identified inhibitors, which overlap with the LPS-binding site on protein MD-2, might represent leading compounds for drug development useful for sepsis treatment and cure of chronic diseases, where receptor complex TLR4 / MD-2 is involved.
Significance for the country
The use and enrichment of our own knowledge is the best way for sustainable development and ensures a high added value and a competitive position. The project is also of medical importance, as it may lead to the improvement of human health and reduction of economic and social damage due to the disease. The results of the project are also interesting for pharmaceutical industry. The research is interdisciplinary, based on the unraveling of basic knowledge from the biotechnological and medicine area, with a potential use for applicative researches within industry.
Most important scientific results
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Most important socioeconomically and culturally relevant results
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