Journal of Clinical and Cellular Immunology
Open Access

Molecular and in vivo studies on new small molecule therapeutics targeting TLR4 by an original mechanism of action

Conference Series LLC Joint International Event on 5^th European Immunology & Innate Immunity

July 21-23, 2016 Berlin, Germany

Francesco Peri

University of Milano Bicocca, Italy

Posters & Accepted Abstracts: J Clin Cell Immunol

Abstract :

Toll like Receptors (TLRs) activation by pathogen associated molecular patterns (PAMPs) is a pivotal molecular event in inflammation and innate immunity and TLRs and their agonists are responsible for the efficacy of almost every vaccine. Conversely, TLRs hyper activation by endogenous factors such as oxidized phospholipids or heat shock proteins is the main cause of many inflammatory and autoimmune diseases. Activating or inhibiting specifically TLRs provides access to a new generation of therapeutics. We developed synthetic molecules able to modulate TLR4 activation and signaling and we studied the mechanism of action (MOA) of these non toxic and drug like compounds. Positively or negatively charged synthetic glycolipids are active in blocking TLR4 activation by specifically targeting the CD14 co receptor. These molecules are very efficient in inhibiting TLR4 activation in cells and in contrasting diseases related to TLR4 hyper activation by infectious and endogenous agents in animal models. We investigated at a molecular level the MOA of these molecules by binding experiments with purified CD14, MD-2 and TLR4 receptors and experiments on dendritic cells, macrophages and HEK-TLR4 cells. The unique MOA of these molecules is based on the capacity to dissociate CD14 and TLR4 endocytosis, thus creating an inducible CD14 deficiency at the cell surface. These conditions are expected to antagonize TLR4 signaling more effectively than simply competing with LPS for CD14 and TLR4. Very promising results have been obtained at a preclinical level using these drug hits and recent (2015) data on animal models of atherosclerosis, neuroinflammation and amyotrophic lateral sclerosis will be reported.