The stimulating adventure of KRN 7000

Abstract

Associated with the CD1d protein, KRN 7000, a potent synthetic α-galactosylceramide, is known to activate the invariant NKT immune cells. This stimulation then leads to the production of different cytokines modulating a T(H)1/T(H)2 immune response balance involved in protection against several pathologies such as autoimmune diseases and cancers. Various efforts have been made toward the synthesis of simple and more functionalized analogues in order to selectively induce T(H)1 or T(H)2-type cytokine production. Since the discovery of KRN 7000, structure-activity relationships, crystallographic and modelling studies have pointed to the potential of several GalCer analogues in term of selective bioactivity, and have highlighted interesting elements in order to better understand the recognition and activation mechanisms of immune iNKT cells. By presenting an up-to-date library of analogues, collecting recent breakthroughs done in crystallography and molecular modelling, and relating them to the available biological results, we hope that this review will highlight and help the scientific community in their KRN research.

Design and Evaluation of ω-Hydroxy Fatty Acids Containing α-GalCer Analogues for CD1d-Mediated NKT Cell Activation

“…[6][7][8]13,23 Previous structural alterations of the α-GalCer fatty acid chain have focused on modulating the hydrophobic interactions. Our ω-hydroxy α-GalCer analogue represents the first example that introduces a hydrogen bonding interaction within the binding groove of the A′ pocket.…”

Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation

“…This lipid binding orientation allows the sugar headgroup to be exposed in the center for recognition by the type I NKT cell TCR, with the ␣ chain of the TCR providing the predominant binding energy (8,9). Many GSLs have been analyzed for the activation of type I NKT cell TCRs, but the most commonly studied is ␣-galactosylceramide (␣GalCer) (10,11). This prototypical glycolipid activates type I NKT cells to secrete both IL-4 and IFN-␥ in vivo within 90 min.…”

Heteroaromatic Moieties in the Sphingosine Backbone of α-Galactosylceramides for Noncovalent Interactions with CD1d

“…11−15 However, the in vivo efficacy of 1 has been somewhat limited because of its dual antagonizing effects on both Th1 and Th2 cytokines, and these dual effects are known to be polar opposites in immune response. 1 In other words, 1 can stimulate the secretion of both pro-and anti-inflammatory cytokines and can result in no net changes in immunity. Thus, many recent studies have focused on the synthesis of KRN7000 analogues that can selectively activate iNKT cells to secrete certain cytokines.…”

“…Thus, many recent studies have focused on the synthesis of KRN7000 analogues that can selectively activate iNKT cells to secrete certain cytokines. 1 For example, the structural modification of the sugar moiety in α-GalCer revealed that the α-anomeric galactose is considerably better than other sugars, such as glucose, mannose, and β-galactose without selectivity. 12 However, the structural modification at the C6 position of the galactosyl moiety in α-GalCer with a 4Cl-3CF 3 -benzamide substituent (2) showed a promising Th1-based polarizing effect.…”

“…9,10 These examples suggest that the decreased stability of the CD1d−α-GalCer complex leads to a Th2 response as a result of to their short retention time at the surface of APCs. 21 Even though the structure−activity relationships of α-GalCer analogues are substantially difficult to predict, 1 we recognized the importance of the binding affinity in the CD1d−α-GalCer complex for the selective activation of either the Th1 or the Th2 response. Unlike the cases of sugar and N-acyl moieties, the extensive modifications of sphingosine backbones have not yet been actively pursued.…”