title: Noncarbohydrate glycomimetics and glycoprotein surrogates as DC-SIGN antagonists and agonists.
abstract: An understanding of the biological roles of lectins will be advanced by ligands that can inhibit or even recruit lectin function. To this end, glycomimetics, noncarbohydrate ligands that function analogously to endogenous carbohydrates, are being sought. The advantage of having such ligands is illustrated by the many roles of the protein DC-SIGN. DC-SIGN is a C-type lectin displayed on dendritic cells, where it binds to mannosides and fucosides to mediate interactions with other host cells or bacterial or viral pathogens. DC-SIGN engagement can modulate host immune responses (e.g., suppress autoimmunity) or benefit pathogens (e.g., promote HIV dissemination). DC-SIGN can bind to glycoconjugates, internalize glycosylated cargo for antigen processing, and transduce signals. DC-SIGN ligands can serve as inhibitors as well as probes of the lectin's function, so they are especially valuable for elucidating and controlling DC-SIGN's roles in immunity. We previously reported a small molecule that embodies key features of the carbohydrates that bind DC-SIGN. Here, we demonstrate that this noncarbohydrate ligand acts as a true glycomimetic. Using NMR HSQC experiments, we found that the compound mimics saccharide ligands: It occupies the same carbohydrate-binding site and interacts with the same amino acid residues on DC-SIGN. The glycomimetic also is functional. It had been shown previously to antagonize DC-SIGN function, but here we use it to generate DC-SIGN agonists. Specifically, appending this glycomimetic to a protein scaffold affords a conjugate that elicits key cellular signaling responses. Thus, the glycomimetic can give rise to functional glycoprotein surrogates that elicit lectin-mediated signaling.
authors: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Lynne R
authors: LR
authors: Prost
authors: Joseph C
authors: JC
authors: Grim
authors: Marco
authors: M
authors: Tonelli
authors: Laura L
authors: LL
authors: Kiessling
mesh_terms: D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry*; D015815:Cell Adhesion Molecules / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D037181:Lectins, C-Type / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D037181:Lectins, C-Type; D008024:Ligands; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin