2^nd Glycobiology World Congress

Biography

Biography: Francesco Peri

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. Converserly, TLRs hyperactivation by endogenous factors such as oxidized phopsholipids 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 signalling and we studied the mechanism of action (MOA) of these non toxic, drug-like compounds. Positively or negatively charged synthetic glycolipids are active in blocking TLR4 activation by specifical targeting the CD14 co-receptor. These molecules are very efficient in inhibiting TLR4 activation in cells and in contrasting diseases related to TLR4 hyperactivation 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 data on animal models of atherosclerosis, neuroinflammation, and amyotrophic lateral sclerosis will be reported.