Synthetic glycolipids targeting caspase-4/11 and TLR4 as a novel strategy for management of inflammation and sepsis.
Abstract
Mammalian immune receptors trigger intracellular pro-inflammatory signaling cascades in response to infectious challenge, which promotes inflammation and contributes to recovery from infection. When bacteria leave the located area to invade the bloodstream (bacteremia), substantial amounts of bacterial Endotoxin is released into the circulation of the host resulting in the over-activation of inflammatory pathways and sepsis syndrome. The malfunction of the regulatory mechanisms during sepsis leads to the loss of control of inflammation and a life-threatening endotoxic shock (sepsis) with extraordinary high 50% mortality rate. Toll-like receptor 4 (TLR4) expressed by the host immune cells propagate the immediate immune response to Gram-negative bacterial infection and plays the central role in the initiation and progression of sepsis. Activation of TLR4 is interrelated with the activation of a newly discovered cytosolic Endotoxin receptor, caspase-4/11, which leads to programmed cell death and is deeply implicated in the development of sepsis. Activation of TLR4 contributes to the pathogenesis of numerous inflammatory, auto-immune and chronic diseases such as asthma, arthritis and cancer which highlights the significance of TLR4 as therapeutic target. Despite tremendous efforts of Pharma R&D to develop anti-sepsis drugs and immuno-modulators, no effective therapeutic remedy has been developed so far. Sepsis is increasingly reputed as the ultimate common pathway to death from infection and remains the leading cause of mortality in intensive care units. In a view of the globally expanding antibiotic resistance, the occurrence and frequency of sepsis is anticipated to rise emphasizing the importance of exploiting new approaches for treatment and prevention of sepsis and chronic inflammation. The objective of the Grant Proposal is to develop a new class of TLR4- and caspase-4/11 – specific sugar-based molecules having pronounced anti-inflammatory properties. Novel generation of innovative glycolipids will be designed, synthesised and biologically evaluated. Synthetic glycolipids based on the sugar scaffolds will block the binding of Endotoxin to respective receptor proteins (antagonist). Chemical modifications of the basic antagonist glycolipid structure will provide molecules with unique biological features - partial agonists at TLR4 and caspase-4/11. Partial agonist will compete with Endotoxin for binding on the receptor proteins, and thereby, block the induction of deleterious pro-inflammatory signaling. At the same time, exposure of TLR4 complex to partial agonist will ensure a constant, weak level of immune activation, preventing in this way the lethal sepsis-induced immunosuppression. This way of immunomodulation is a promising strategy for therapy of acute and chronic diseases ranging from autoimmune disorders to antibiotic-resistant infections. The project will be performed within tight cooperation between bioorganic chemists (BOKU), immunologists and molecular and structural biologists (cooperation partners in Germany, Belgium, USA and China). The research project will contribute to understanding of molecular mechanisms of inflammatory diseases and will foster the invention of novel sugar-based immunotherapeutics directed to the resolution of inflammation and treatment of sepsis.
Publikationen
Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity
Autoren: Arenas, J; Pupo, E; Phielix, C; David, D; Zariri, A; Zamyatina, A; Tommassen, J; van der Ley, P; Jahr: 2020
Journal articles
Synthesis of bioactive lipid A and analogs
Autoren: Alla Zamyatina; Sebastian Strobl Jahr: 2020
Chapter in collected volumes
Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
Autoren: Zamyatina, A; Heine, H; Jahr: 2020
Journal articles
Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.
Autoren: Heine, H; Adanitsch, F; Peternelj, TT; Haegman, M; Kasper, C; Ittig, S; Beyaert, R; Jerala, R; Zamyatina, A; Jahr: 2021
Journal articles
Rational Vaccine Design in Times of Emerging Diseases: The Critical Choices of Immunological Correlates of Protection, Vaccine Antigen and Immunomodulation.
Autoren: Schijns, V; Majhen, D; van der Ley, P; Thakur, A; Summerfield, A; Berisio, R; Nativi, C; Fernández-Tejada, A; Alvarez-Dominguez, C; Gizurarson, S; Zamyatina, A; Molinaro, A; Rosano, C; Jakopin, Ž; Gursel, I; McClean, S; Jahr: 2021
Journal articles
Orchestrating TLR4 signaling and caspase-4/11 activation with endotoxin mimetics
Autoren: Alla Zamyatina Jahr: 2020
Conference & Workshop proceedings, paper, abstract
Project staff
Alla Zamyatina
Assoc. Prof. Dipl.-Ing. Dr. Alla Zamyatina
alla.zamyatina@boku.ac.at
Tel: +43 1 47654-77384
Project Leader
01.05.2019 - 30.06.2023
Alessandro Monti
Alessandro Monti MSc.
alessandro.monti@boku.ac.at
Tel: +43 1 47654-77331, 79023
Project Staff
01.05.2019 - 24.04.2023
Project Staff
25.04.2023 - 30.06.2023
Tomas Vasicek
Tomas Vasicek MSc.
tomas.vasicek@boku.ac.at
Project Staff
01.05.2019 - 24.04.2023
Project Staff
25.04.2023 - 30.06.2023
Daniele Zucchetta
Daniele Zucchetta MSc.
daniele.zucchetta@boku.ac.at
Tel: +43 1 47654-77331
Project Staff
01.05.2019 - 24.04.2023
Project Staff
25.04.2023 - 30.06.2023