Diamino Allose Phosphates: Novel, Potent, and Highly Stable Toll-like Receptor 4 Agonists

Abstract

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydratebased lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.

Adjuvanted Vaccine Induces Functional Antibodies against Pseudomonas aeruginosa Filamentous Bacteriophages

“…Previous studies identified the importance of lipopolysaccharide (LPS) engagement of TLR4 in the clearance of Pa infections [ 21 ], and thus we hypothesized that the use of a TLR4 agonist would enhance an antibody response specific to CoaB. A component of LPS, Lipid A, is the bioactive element and is the structural basis of our synthetic TLR4 agonist, INI-2002 ( Figure 1 E) [ 13 , 22 ].…”

“…Adjuvants bound to PRRs can result in the production of specific cytokines and cell-surface proteins, which can enhance adaptive immunity when co-administered with an antigen [ 12 ]. The lead adjuvant described herein, INI-2002, is a synthetic TLR4 agonist that enhances both cell-mediated and humoral immunity [ 13 ]. Animals vaccinated with the CoaB peptide conjugated to CRM197 and adjuvanted with INI-2002 had increased antigen-specific antibody production when compared to animals vaccinated with the CoaB conjugate adsorbed to Alhydrogel.…”