# Identification and Evaluation of Benzimidazole- Agonists of Innate Immune Receptor NOD2

## TL;DR

This paper identifies benzimidazole compounds, including nocodazole, as new NOD2 agonists that could improve immune-related therapies.

## Contribution

The discovery of benzimidazoles as a novel class of NOD2 agonists with potential therapeutic advantages over existing MDP-based agonists.

## Key findings

- Benzimidazoles, including nocodazole, activate NOD2 with nanomolar potency.
- Nocodazole induces cytokine release similar to MDP-based NOD2 activation.
- Benzimidazole agonists may offer better pharmacological properties than current MDP derivatives.

## Abstract

Emerging evidence has demonstrated the importance of
pattern recognition
receptors (PRRs), including the nucleotide-binding and oligomerization
domain receptor 2 (NOD2), in human health and disease states. NOD2
activation has shown promise with aiding malnutrition recovery, lessening
irritable bowel disease (IBD) symptoms, and increasing the efficacy
of cancer immunotherapy. Currently, most NOD2 agonists are derivatives
or analogs of the endogenous agonist derived from bacterial peptidoglycan,
muramyl dipeptide (MDP). These MDP-based agonists can suffer from
low oral bioavailability and cause significant adverse side effects.
With the goal of broadly improving NOD2 therapeutic interventions,
we sought to discover a small molecule capable of activating NOD2
by screening a library of total 1917 FDA approved drugs in a phenotypic
assay. We identified a class of compounds, benzimidazoles, that act
as NOD2 agonists, with the most potent member of this class being
nocodazole. Nocodazole activates NOD2 with nanomolar potency and causes
the release of cytokines canonically associated with MDP-induced NOD2
activation, suggesting its potential to elicit similar therapeutic
immune effects as MDP and potentially offer improved pharmacological
properties.