Peptide inhibitors of xenoreactive antibodies mimic the interaction profile of the native carbohydrate antigens.
Carbohydrate-antibody interactions mediate many cellular processes and immune responses. Carbohydrates expressed on the surface of cells serve as recognition elements for particular cell types, for example, in the ABO(H) blood group system. Antibodies that recognize host-incompatible ABO(H) system antigens exist in the bloodstream of all individuals (except AB individuals), preventing blood transfusion and organ transplantation between incompatible donors and recipients. A similar barrier exists for cross-species transplantation (xenotransplantation), in particular for pig-to-human transplantation. All humans express antibodies against the major carbohydrate xenoantigen, Galalpha (1,3)Gal (alphaGal), preventing successful xenotransplantation. Although antibody binding sites are precisely organized so as to selectively bind a specific antigen, many antibodies recognize molecules other than their native antigen. A range of peptides have been identified that can mimic carbohydrates and inhibit anti-alphaGal antibodies. However, the structural basis of how the peptides achieved this was not known. Previously, we developed an in silico method which we used to investigate carbohydrate recognition by a panel of anti-alphaGal antibodies. The method involves molecular docking of carbohydrates to antibodies and uses the docked carbohydrate poses to generate maps of th antibody binding sites in terms of prevalent hydrogen bonding and van der Waals interactions. We have applied this method to investigate peptide recognition by the anti-alphaGal antibodies. It was found that the site maps of the peptides and the carbohydrates were similar, indicating that the peptides interact with the same residues as those involved in carbohydrate recognition. This study demonstrates the potential for "design by mapping" of anti-carbohydrate antibody inhibitors.
Agostino
Mark
M
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Sandrin
Mauro S
MS
Thompson
Philip E
PE
Ramsland
Paul A
PA
Yuriev
Elizabeth
E
D000017:ABO Blood-Group System / Q000737:chemistry* / Q000276:immunology; D040761:Biomimetic Materials / Q000737:chemistry*; D002241:Carbohydrates / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000737:chemistry* / Q000276:immunology; D010455:Peptides / Q000737:chemistry* / Q000276:immunology
D000017:ABO Blood-Group System; D002241:Carbohydrates; D007518:Isoantibodies; D010455:Peptides