Research

Development of NOD2 agonists and dual NOD2/TLR7 agonistic conjugates as novel vaccine adjuvants

Code:

J3-9256

Range:

01. July 2018 - 30. June 2022

Range:

0,75 FTE

Leader:

Žiga Jakopin

Field:

3.01 Medical sciences/ Microbiology and immunology

Abstract:

Currently, our world is facing an acute shortage of novel vaccine adjuvants. Adjuvants enhance the immunogenicity of vaccines, therefore they constitute essential components of vaccines. They are needed not only to increase the magnitude of the response but also to guide the type of response to produce the most effective type of immunity against distinct pathogens/tumors. The recent progress in our understanding of innate immunity and its potential for tailoring adaptive immunity has opened up new avenues for vaccine development. Pattern recognition receptors (PRRs) are evolutionarily conserved innate immune sensors that orchestrate the initial defense response as part of the innate immune process. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), that belongs to a cytosolic class of PRRs, the NOD-like receptors (NLR), plays a key role in both innate as well as adaptive immunity. Muramyl dipeptide (MDP) is the smallest structural subunit of bacterial peptidoglycan capable of eliciting NOD2 activation, and known as an effective adjuvant, however its use has been abandoned due to several drawbacks (rapid elimination, low absorption and pyrogenicity). Up until now, structure-based design has not been used in the discovery of NOD2 ligands. The crystal structure of rabbit NOD2 was only recently determined and a hydrophobic pocket proposed as a potential MDP-binding site. Moreover, the homology model of human NOD2, which would allow for structure-based design of NOD2 ligands as well as screening for non-peptide fragments with high binding affinity, has yet to be constructed. Thus, no small molecule NOD2 agonists of non-peptide nature have been reported. Desmuramylpeptides are MDP derivatives lacking the sugar Nacetylmuramyl moiety (MurNAc). Our past work established the essential structural requirements of desmuramylpeptides for achieving NOD2 agonistic activity, identifying transferuloyl moiety as an excellent MurNAc mimetic. Although our best compound was twice as potent as MDP in vitro, it proved to be a weaker adjuvant in vivo, due to ester hydrolysis, affording free acid, a much weaker NOD2 agonist. While activation of NOD2 itself is sufficient to shape adaptive immune responses, more importantly, NOD2 agonists synergistically amplify the adjuvant potential of other PRR ligands such as Toll-like receptor (TLR) ligands and alters the magnitude, persistence and the type of response.