Nonpeptide Ligands That Target Peptide-Activated GPCRs In Inflammation

Abstract

The focus of this review is on G protein-coupled receptors (GPCRs) for which nonpeptidic ligands are known and have been evaluated for the treatment of inflammatory conditions. GPCRs are the most prevalent class of cell surface proteins in pharmaceutical research today, and GPCR-targeting drugs account for one tenth of worldwide pharmaceutical sales. Of over 800 human GPCRs identified to date, several hundred are activated by peptides/proteins and just over 30 of these have been identified so far as potential therapeutic targets for the treatment of inflammatory diseases. This review highlights those GPCRs and over 60 structurally diverse nonpeptidic compounds that interact with them and display pro- or anti- inflammatory properties. Among these GPCR targets are the receptors for peptides like bradykinin, chemokines, complement anaphylatoxins, corticotropin releasing factor, endothelins, melanocortins, tachykinins, urocortins, as well as the protease activated receptors (PARs). Other peptide activated GPCRs implicated in inflammation, like those that bind angiotensin II, N-formyl peptides, galanin, neuropeptide Y, opioids and oxytocin, are only briefly discussed because there is either less direct association with inflammation or few/no nonpeptidic antiinflammatory ligands known. While it is still very early in the development of antiinflammatory drugs that target GPCRs, there is already a wealth of information supporting their important roles as cellular sentries in inflammatory diseases. New opportunities are emerging to evaluate antiinflammatory activities of potent and selective GPCR-binding ligands, including those being developed for other disease indications. In summary, GPCRs deserve a great deal more attention as potential therapeutic targets in inflammatory diseases.

Neuropeptides as Pleiotropic Modulators of the Immune Response

“…However, in the case of the type 2 G-protein-coupled receptors (i.e. receptors for VIP, UCN and AM), the pharmaceutical industry has so far failed to generate effective specific non-peptide agonists [102]. Understanding the structure-function relationship of these neuropeptides and their specific receptors – including receptor signaling, internalization, and homo- and heterodimerization in physiological and pathologic situations – will facilitate the development of novel pharmacological agents.…”

ERα-negative and triple negative breast cancer: Molecular features and potential therapeutic approaches

“…These data have established an important role for miRNA-7 in controlling EGFR mRNA expression and have indicated that miRNA-7 has the ability to coordinately regulate EGFR signaling in multiple human cancer breast cancer cells, particularly in TNBC and glioblastoma [76, 77]. Non-peptide ligands that target peptide-activated GPCRs have been developed for treatment of inflammation and obesity [78, 79]. It is likely that development of antagonists selective for GPCR-30 deserves a great potential as therapeutic targets in TNBC.…”

Anti-inflammatory neuropeptides: A new class of endogenous immunoregulatory agents

“…An attractive strategy is the development of nonpeptide receptor agonists. However, in the case of the type 2 GPCRs, including VIP, urocortin, αMSH and adrenomedullin receptors, the pharmaceutical industry has so far failed to generate effective nonpeptide-specific agonists (Blakeney and Fairlie, 2005). Even where synthetic agonists were designed specifically for VIP receptors, they were less effective than the natural peptide in terms of anti-inflammatory activity (Delgado et al, 2004).…”