Modulating the RAGE‐Induced Inflammatory Response: Peptoids as RAGE Antagonists

Abstract

While the primary pathology of Alzheimer’s disease (AD) is defined by brain deposition of amyloid‑β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end‐products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD‐associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood‐brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V‐domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide‐induced pro‐inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid‐based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.

The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases

“…In this regard, some new efforts have been focused on the development of inhibitors of RAGE binding and signaling, as well as those that could be useful in the treatment of RAGE activation-associated diseases [202][203][204][205].…”

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells

“…Studies have shown novel therapeutic opportunities of peptidomimetics modulating cell signaling pathways [23,24], neuroinflammation [25,26], oxidative stress [27], apoptosis [28,29], and depression [21,30,31]. For example, peptoids such as RAGEs (receptor for advanced glycation end-products) antagonists can modulate the RAGE-induced inflammatory response [26]. A structure-based development of new peptidomimetic cyclic compounds was conducted for the PSD-95 PDZ3 domain, which is a promising therapeutical target for depression [32].…”