Medicinal chemistry of the myeloid C-type lectin receptors Mincle, Langerin, and DC-SIGN

Abstract

In their role as pattern-recognition receptors on cells of the innate immune system, myeloid C-type lectin receptors (CLRs) assume important biological functions related to immunity, homeostasis, and cancer. As such,...

Lipophilic glucose monoesters and glycosides are potent human Mincle agonists

“…However, GlcC14C18 ( 3 ) retained its activity with the mutant, as did the docosylated branched glycolipids C14C18GlcαOC22 ( 9 ) and C14C18GlcβOC22 ( 10 ). Since the QPD motif confers binding to galactose residues instead of glucose residues, 41 this outcome was surprising and might indicate strong lipid binding to the primary and/or secondary lipophilic binding sites in Mincle 16 in addition to the CRD.…”

“…3,13 As changes to Mincle ligands can influence the immunological activity of the compounds, much research has been undertaken to identify the structural requirements for optimal Mincle binding and activation. [14][15][16] Mincle contains a carbohydrate recognition domain (CRD), 17,18 which recognises many pathogen-associated molecular patterns, 14 as well as a cholesterol recognition amino acid consensus (CRAC) motif 19 that is found in human Mincle (hMincle, Fig. 2) but not murine Mincle (mMincle), 20 and which binds cholesterol metabolites.…”

“…This latter point is important, for while Mincle signaling provides an indication of agonist activity, it does not always reveal the functional potency of a ligand or the manner in which a ligand skews the immune response. 16,25,33,34…”

“…Mincle can accommodate a wide variety of ligands, 14–16 however, of interest to us was the observation that glucose monoesters such as GlcC14C18 ( 3 ), 27 and lipidated brartemicin derivatives such as C18dMeBrar ( 4 ), 25,28 are potent Mincle agonists. For both classes of ligand, computational studies suggested binding of one pyranose ring to the EPN motif.…”

Drug-like Inhibitors of DC-SIGN Based on a Quinolone Scaffold

“…15,16 Despite growing pharmaceutical interest, the discovery of potent inhibitors targeting DC-SIGN, as well as CLRs in general, has been hampered by the hydrophilic and shallow nature of the carbohydrate binding site (CBS), which results in low intrinsic affinities for its carbohydrate ligands. 2,17 For example, the affinity of DC-SIGN for its monovalent carbohydrate ligand, mannose, is 3.5 mM. 15 Furthermore, since carbohydrates do not bear hydrophobic groups and mainly rely on hydrogen bonding with the CBS, their pharmacological properties are insufficient to consider them as drug-like.…”