Discovery of Desmuramylpeptide NOD2 Agonists with Single-Digit Nanomolar Potency

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Aug 18

PMID 35978688

Authors

Samo Guzelj

Spela Bizjak

Ziga Jakopin

Affiliations

Soon will be listed here.

Abstract

The innate immune receptor nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) represents an important target for the development of structurally defined small molecule immunomodulatory compounds that have great potential to be used either as vaccine adjuvants or as general immunostimulatory agents. We report here the investigation of the structure-activity relationship of a series of novel desmuramylpeptide NOD2 agonists. Extensive exploration of chemical space culminated in the discovery of a lipophilic adamantane-moiety-featuring compound , the first single-digit nanomolar and the most potent NOD2 agonist in its structural class to date. Moreover, acted synergistically with lipopolysaccharide and interferon-γ to induce the production of cytokines in human peripheral blood mononuclear cells and enhance their nonspecific cytotoxic activity against K562 cancer cells. These findings provide initial insight into its immunostimulatory potential, especially when used in combination with other immunopotentiators.

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