Enhancing Potency and Selectivity of a DC‐SIGN Glycomimetic Ligand by Fragment‐Based Design: Structural Basis

Abstract

Chemical modification of pseudo‐dimannoside ligands guided by fragment‐based design allowed for the exploitation of an ammonium‐binding region in the vicinity of the mannose‐binding site of DC‐SIGN, leading to the synthesis of a glycomimetic antagonist (compound 16) of unprecedented affinity and selectivity against the related lectin langerin. Here, the computational design of pseudo‐dimannoside derivatives as DC‐SIGN ligands, their synthesis, their evaluation as DC‐SIGN selective antagonists, the biophysical characterization of the DC‐SIGN/16 complex, and the structural basis for the ligand activity are presented. On the way to the characterization of this ligand, an unusual bridging interaction within the crystals shed light on the plasticity and potential secondary binding sites within the DC‐SIGN carbohydrate recognition domain.

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

“…[110,111] In addition, these modifications also take advantage of the shallower and more acidic binding area of DC-SIGN to hinder langerin recognition, thereby enhancing DC-SIGN selectivity. [111] The elongation of the mannobioside with a third reducing Man improves the affinity as well, although the binding pose and contacts were found to be identical to those for the mannobiose analogue as revealed by X-ray crystallography. [112] This is a fairly particular case, as this ligand displays two available Man residues and hence its higher affinity expectedly arises from multiple binding ( Figure 5, bottom).…”

“…These two side chains have been actually exploited for the design of bulky and positive substituents which can preclude binding to langerin while still targeting DC-SIGN, thereby improving the selectivity for the latter. [110,111] Even so, the development of novel specific and potent sugar mimetics remains challenging given that the intrinsic CRD architecture displays very exposed and polar surfaces that are rather undruggable, as already suggested by computational methods. [147] Of course, screening techniques are suitable to reduce the time costs in this quest, but require from the appropriated setup to undertake a reliable and fast enough evaluation of large libraries.…”

“…Such a structure could be anticipated to bind through the outer Man, mimicking the minor mode described for Manα1‐2Man, [107] but X‐ray and NMR data interestingly supported the opposite orientation, in which the “reducing” aliphatic ring is located on top of Val351 [108] . Following these observations, the subsequent chemical modifications were placed to increase the ligand contacts with the long loop [109] and with the secondary site (Phe313), by adding molecular fragments at C2 or C6 of the nonreducing Man [110,111] . In addition, these modifications also take advantage of the shallower and more acidic binding area of DC‐SIGN to hinder langerin recognition, thereby enhancing DC‐SIGN selectivity [111] .…”

“…Following these observations, the subsequent chemical modifications were placed to increase the ligand contacts with the long loop [109] and with the secondary site (Phe313), by adding molecular fragments at C2 or C6 of the nonreducing Man [110,111] . In addition, these modifications also take advantage of the shallower and more acidic binding area of DC‐SIGN to hinder langerin recognition, thereby enhancing DC‐SIGN selectivity [111] . The elongation of the mannobioside with a third reducing Man improves the affinity as well, although the binding pose and contacts were found to be identical to those for the mannobiose analogue as revealed by X‐ray crystallography [112] .…”

One pot synthesis ofthio-glycosidesviaaziridine opening reactions

“…1 To overcome at least some of these drawbacks, chemically modified analogues of natural carbohydrates, so called glycomimetics, have been proposed. 2 The development of functional carbohydrate mimics has been tackled either by structure-based design, 1,[3][4][5][6][7][8][9][10][11][12][13] or by discovery campaigns, often planned taking advantage of microarray technology. [14][15][16] The latter approach has been frustrated by the cumbersome synthesis of oligosaccharides, that severely limits the diversity and the number of compounds that can be rapidly generated.…”