Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN.
It is widely accepted that the heavily glycosylated glycoprotein gp120 on the surface of HIV-1 shields peptide epitopes from recognition by the immune system and may promote infection in vivo by interaction with dendritic cells and transport to tissue rich in CD4(+) T cells such as lymph nodes. A conserved cluster of oligomannose glycans on gp120 has been identified as the epitope recognized by the broadly HIV-1-neutralizing monoclonal antibody 2G12. Oligomannose glycans are also the ligands for DC-SIGN, a C-type lectin found on the surface of dendritic cells. Multivalency is fundamental for carbohydrate-protein interactions, and mimicking of the high glycan density on the virus surface has become essential for designing carbohydrate-based HIV vaccines and antiviral agents. We report an efficient synthesis of oligomannose dendrons, which display multivalent oligomannoses in high density, and characterize their interaction with 2G12 and DC-SIGN by a glycan microarray binding assay. The solution and the surface binding analysis of 2G12 to a prototype oligomannose dendron clearly demonstrated the efficacy of dendrimeric display. We further showed that these glycodendrons inhibit the binding of gp120 to 2G12 and recombinant dimeric DC-SIGN with IC(50) in the nanomolar range. A second-generation Man(9) dendron was identified as a potential immunogen for HIV vaccine development and as a potential antiviral agent.
Wang
Sheng-Kai
SK
Departments of Chemistry and Immunology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Liang
Pi-Hui
PH
Astronomo
Rena D
RD
Hsu
Tsui-Ling
TL
Hsieh
Shie-Liang
SL
Burton
Dennis R
DR
Wong
Chi-Huey
CH
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D050260:Carbohydrate Metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005434:Flow Cytometry; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000378:metabolism*; D008358:Mannose / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D050091:Dendrimers; D037181:Lectins, C-Type; D008358:Mannose; D011108:Polymers; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin