Toll-Like Receptor 4 (TLR4) is one of the receptors of innate immunity, it is activated by Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs), and triggers pro-inflammatory responses which belong to the repertoire of innate immune responses, thus protecting against infectious challenges and boosting adaptive immunity. Mild TLR4 stimulation by non-toxic molecules resembling its natural agonist (lipid A), provided efficient vaccine adjuvants. The non-toxic TLR4 agonist monophosphoryl lipid A (MPLA) has been approved for clinical use, thus suggesting the development of other TLR4 agonists as adjuvants or drugs for cancer immunotherapy. TLR4 excessive activation by Gram-negative bacteria lipopolysaccharide (LPS) leads to sepsis, while TLR4 stimulation by DAMPs is a common mechanism in several inflammatory and autoimmune diseases. TLR4 inhibition by small molecules and antibodies could therefore provide access to innovative therapeutics targeting sepsis, acute and chronic inflammations. TLR4 antagonists can also block the violent inflammation and cytokine storm caused by several viral diseases, including COVID-19.<br/>The most recent achievement of our group in the development of synthetic glycolipids with activity as TLR4 agonists and antagonists (FP molecules) will be presented: computer-assisted rational design, in vitro binding studies with the receptor, cell and in vivo activity, studies on the mechanism of action.<br/>New TLR4 agonists with a monosaccharide structure mimic the pharmacophore of lipid A and MPLA, and potently stimulate innate immunity and are in preclinical development as adjuvants in antiviral and antibacterial vaccines (www.bactivax.eu). Monosaccharide antagonist FP7 efficiently blocked inflammation in cell models and in animal models of sepsis, influenza virus lethality, vascular inflammations, neuroinflammations, and inflammatory bowel diseases (IBDs).

Synthetic, sugar-based Toll-like Receptor 4 (TLR4) modulators: new drug leads targeting infectious and inflammatory diseases

ACS Spring Meeting 2021

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