Therapeutic potential of targeting the receptor for advanced glycation end products (RAGE) by small molecule inhibitors

Abstract

Receptor for advanced glycation end products (RAGE) is a 45 kDa transmembrane receptor of immunoglobulin family that can bind to various endogenous and exogenous ligands and initiate the inflammatory downstream signaling pathways. RAGE is involved in various disorders including cardiovascular and neurodegenerative diseases, cancer, and diabetes. This review summarizes the structural features of RAGE and its various isoforms along with their pathological effects. Mainly, the article emphasized on the translational significance of antagonizing the interactions of RAGE with its ligands using small molecules reported in the last 5 years and discusses future approaches that could be employed to block the interactions in the treatment of chronic inflammatory ailments. The RAGE inhibitors described in this article could prove as a powerful approach in the management of immune-inflammatory diseases. A critical review of the literature suggests that there is a dire need to dive deeper into the molecular mechanism of action to resolve critical issues that must be addressed to understand RAGE-targeting therapy and long-term blockade of RAGE in human diseases.

Keywords: AGEs; RAGE; RAGE isoforms; S100 proteins; antagonist; chronic inflammatory diseases; endogenous ligands; exogenous ligands; inhibitor.

Figure 1

(a) Mechanisms of glycation to produce AGEs and (b) Ligand binding with RAGE and the downstream signaling pathways. AGEs, advanced glycation end products; RAGE, receptor for advanced glycation end products

Figure 2

(Left) Full‐length RAGE and its various isoforms: Full‐length RAGE consists of Variable domain (V‐domain), two constant domains (C1 and C2), transmembrane domain, and cytoplasmic domain; its isoforms dominant negative RAGE (DN‐RAGE), N‐truncated RAGE (N‐RAGE), and secretory or soluble RAGE (sRAGE) with their respective domains. (Right) Various extracellular and intracellular ligands binding with RAGE. RAGE, receptor for advanced glycation end products

Figure 3

Molecular structure of various RAGE inhibitors that bind to its extracellular domain. RAGE, receptor for advanced glycation end products

Figure 4

Co‐crystallized structure of RAGE VC1 domain with bound compounds 8–10 and their binding orientations with three different binding sites. RAGE, receptor for advanced glycation end products

Figure 5

(a) Molecular structure of various RAGE inhibitors that bind to its intracellular domain; (b) Structure of RAGE inhibitors with unknown mechanism. RAGE, receptor for advanced glycation end products