Chimeric NOD2 Mincle Agonists as Vaccine Adjuvants

Abstract

There is a need for improved vaccine adjuvants to augment vaccine efficacy. One way to address this is by targeting multiple immune cell pathogen recognition receptors (PRRs) using chimeric pathogen-associated molecular patterns (PAMPs). Conjugation of the PAMPs will ensure codelivery of the immunostimulatory molecules to the same cell, enhancing adjuvant activity. The macrophage inducible C-type lectin (Mincle) is a promising PRR for adjuvant development; however, no effective chimeric Mincle adjuvants have been prepared. We addressed this by synthesizing Mincle adjuvant conjugates, MDP-C18Brar and MDP-C18Brar-dilipid, which contain PAMPs recognized by Mincle and the nucleotide-binding oligomerization domain 2 (NOD2). The two PAMPs are joined by a pH-sensitive oxyamine linker which, upon acidification at lysosomal pH, hydrolyzed to release the NOD2 ligands. The conjugates elicited the production of Th1 and Th17 promoting cytokines in vitro, and when using OVA as a model antigen, exhibited enhanced T-cell-mediated immune responses and reduced toxicity in vivo, compared to the coadministration of the adjuvants.

Probing Isosteric Replacement for Immunoadjuvant Design: Bis-Aryl Triazole Trehalolipids are Mincle Agonists

“…To gain further insight into the mode of binding of 1c to Mincle, molecular docking of this compound was undertaken using the Schrödinger software suite . As observed for other trehalose diesters, the trehalose core of 1c bound to the Ca 2+ ion and the EPN motif in the CRD of hMincle, , while lipid chains occupied adjacent hydrophobic binding grooves (Leu-176/Phe198 and Val167/Ser186; Figure ). In addition, the close proximity between the triazole ring and Arg183 could provide additional binding interactions and thereby improve the overall affinity of this type of ligand for Mincle.…”