Non-carbohydrate inhibitors of the lectin DC-SIGN.
The C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is found on the surface of dendritic cells. It can mediate adhesion between dendritic cells and T lymphocytes and facilitate antigen capture and presentation. Many pathogens can exploit DC-SIGN binding for nefarious purposes. For example, DC-SIGN can facilitate the dissemination of viruses, like HIV-1. Alternatively, some microbes (e.g., Mycobacterium tuberculosis) use their ability to interact with DC-SIGN to evade immune detection. The diverse roles attributed to DC-SIGN provide impetus to identify ligands that can be used to explore its different functions. Such compounds also could serve as therapeutic leads. Most of the DC-SIGN ligands studied previously are mannose- or fucose-derived monosaccharides or oligosaccharides with inhibitory constants in the range of 0.1-10 mM. To identify monovalent ligands with more powerful DC-SIGN blocking properties, we devised a high-throughput fluorescence-based competition assay. This assay afforded potent non-carbohydrate, small molecule inhibitors (IC50 values of 1.6-10 microM). These compounds block not only DC-SIGN-carbohydrate interactions but also DC-SIGN-mediated cell adhesion. Thus, we anticipate that these non-carbohydrate inhibitors can be used to illuminate the role of DC-SIGN in pathogenesis and immune function.
Borrok
M Jack
MJ
Department of Biochemistry and Chemistry, University of Wisconsin, Madison, WI 53706, USA.
Kiessling
Laura L
LL
D000818:Animals; D002241:Carbohydrates / Q000737:chemistry*; D002417:Cattle; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003713:Dendritic Cells / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D037102:Lectins / Q000737:chemistry*; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008968:Molecular Conformation; D009005:Monosaccharides / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D012995:Solubility; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D009005:Monosaccharides; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; D012709:Serum Albumin; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin