title: Unique DC-SIGN clustering activity of a small glycomimetic: A lesson for ligand design.
abstract: DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes highly glycosylated ligands expressed on the surface of various pathogens. This receptor plays an important role in the early stages of many viral infections, including HIV, which makes it an interesting therapeutic target. Glycomimetic compounds are good drug candidates for DC-SIGN inhibition due to their high solubility, resistance to glycosidases, and nontoxicity. We studied the structural properties of the interaction of the tetrameric DC-SIGN extracellular domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured by SPR competition experiments, was 1 order of magnitude higher than that of 1, crystal structures of the complexes within the DC-SIGN carbohydrate recognition domain showed the same binding mode for both compounds. Moreover, when conjugated to multivalent scaffolds, the inhibitory potencies of these compounds became uniform. Combining isothermal titration microcalorimetry, analytical ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN ECD interaction with these glycomimetics revealed that 2 is able, without any multivalent presentation, to cluster DC-SIGN tetramers leading to an artificially overestimated inhibitory potency. The use of multivalent scaffolds presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of potency of 2 upon conjugation and the equal efficacy of chemically simpler compound 1. This study documents a unique case where, among two active compounds chemically derived, the compound with the lower apparent activity is the optimal lead for further drug development.
authors.affiliation: Univ. Grenoble Alpes, Institut de Biologie Structurale (IBS) , Grenoble F-38027, France.
authors.forename: Ieva
authors.initials: I
authors.lastname: Sutkeviciute
authors.forename: Michel
authors.initials: M
authors.lastname: Thépaut
authors.forename: Sara
authors.initials: S
authors.lastname: Sattin
authors.forename: Angela
authors.initials: A
authors.lastname: Berzi
authors.forename: John
authors.initials: J
authors.lastname: McGeagh
authors.forename: Sergei
authors.initials: S
authors.lastname: Grudinin
authors.forename: Jörg
authors.initials: J
authors.lastname: Weiser
authors.forename: Aline
authors.initials: A
authors.lastname: Le Roy
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Reina
authors.forename: Javier
authors.initials: J
authors.lastname: Rojo
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.forename: Christine
authors.initials: C
authors.lastname: Ebel
authors.forename: Franck
authors.initials: F
authors.lastname: Fieschi
mesh_terms: D001665:Binding Sites; D032701:Biomimetics; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008362:Mannosides / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013816:Thermodynamics; D014461:Ultracentrifugation; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008362:Mannosides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin