RS09/Toll Like Receptor (TLR) 4 agonist – APPHALS

RS09/Toll Like Receptor (TLR) 4 agonist – APPHALS Toll Like Receptors (TLRs) Toll Like Receptors (TLRs) are an important family of type I transmembrane Pattern Recognition Receptors (PRRs) that play a key role in activating and linking the innate immune system to adaptive immunity, by sensing invading pathogens or endogenous damage signals. TLRs are expressed on sentinel cells, including macrophages and dendritic cells, and there are ten functional receptors in human (TLR1–10) and twelve in mice (TLR1−9,11−13) . TLR4 and LPS recognition When TLRs are activated, they recruit specific adaptor proteins into the cytosol of immune cells. These adaptors act as messengers to activate transcription factors NF-κB and IRFs, which are the two major effectors of the Innate Immune Response (IIR) . Among membrane-based TLRs, TLR4 is well known for recognizing lipopolysaccharides (LPS) on myeloid cells surface. These cells express LY96 (or MD-2) and CD14 proteins at high level, which are used in collaboration with TLR4 to mediate signal transduction. TLR4 3D structure Recruitment of intracellular adaptor proteins requires dimerization of the TLR4/MD-2 complex, initiated by LPS binding to Lipopolysaccharide Binding Proteins (LBPs) . This LPS-LBP complex will then be recognized by CD14 that will transfer LPS to MD-2, which is associated with TLR4 on the cell surface and without which LPS recognition by TLR4 would fail. RS09 agonist – APPHALS peptide APPHALS peptide is an LPS agonist used as vaccine’s adjuvant to increase antibody production in-vivo. Nowadays, most of the vaccines are formulated with aluminum-based adjuvants that lead to various side effects. The aim of adjuvants being to catalyze innate immune response by stimulating the interactions between antigens and TLR proteins, new TLR agonists based on bacterial material appeared as natural candidate. lipopolysaccharide structure LPS being a key component of gram negative bacteria cell walls triggering TLR4 activation, the use of synthetic LPS peptides to mimic LPS-TLR4 interaction has emerged as a promising alternative adjuvant.