Designing inhibitors of DC-SIGN (dendritic cell-specific intracellular adhesion molecule 3 [ICAM-3]-grabbing non-integrin) as a route to exploring its biological properties

BIOL 32

Kathleen C. Alfare, alfare@chem.wisc.edu1, Erin E. Carlson, carlsone@scripps.edu1, M. Jack Borrok, jborrok@biochem.wisc.edu2, and Laura L. Kiessling3. (1) Department of Chemistry, University of Wisconsin - Madison, 1101 University Avenue, Madison, WI 53706, (2) Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, (3) Departments of Chemistry and Biochemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706
To initiate an immune response, dendritic cells degrade microorganisms and display the resulting antigens to T-lymphocytes. Several transmembrane receptors are involved in these functions, including DC-SIGN. Certain pathogens, such as HIV-1, exploit interactions with DC-SIGN to avoid degradation and enhance their infectivity; therefore, DC-SIGN is an interesting target. It is a C-type lectin, a member of the class of Ca2+-dependent carbohydrate-binding proteins, and is known to bind mannosides. We are pursuing the synthesis and screening of a directed library of glycomimetics designed to bind to C-type lectins like DC-SIGN. We developed a solid phase strategy to synthesize compounds that share a common arrangement of hydroxyl groups yet possess three points of diversity: variation of the amino acid substituent (R1), 1,4-conjugate addition of dithiols (R2), and reaction of benzyl and alkyl bromides with the free thiol (R3). These compounds were assessed for DC-SIGN binding using a high-throughput fluorescence-based competition assay.

 

Frontiers in Chemical Biology
5:00 PM-7:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Biological Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007