RESUMO
Glycosylation is the most common form of post-translational modifications by which oligosaccharide side chains are covalently attached to specific residues of the core protein. Especially O-linked glycan structures like the glycosaminoglycans were found to contribute significantly to many (patho-)biological processes like inflammation, coagulation, cancer and viral infections. Glycans exert their function by interacting with proteins thereby changing the structure of the interacting proteins and consequently modulating their function. Given the complex nature of cell-surface and extracellular matrix glycan structures, this therapeutic site has been neglected for a long time, the only exception being the antithrombin III-glycan interaction which has been successfully targeted by unfractionated and low-molecular weight heparins for many decades. Due to the recent breakthrough in the '-ome' sciences, among them proteomics and glycomics, protein-glycan interactions became more amenable for therapeutic approaches so that novel inhibitors of this interaction are currently in preclinical and clinical studies. An overview of current approaches, their advantages and disadvantages, is given and the promising potential of pharmacologically interfering with protein-glycan interactions is highlighted here.
Assuntos
Desenho de Fármacos , Glicosaminoglicanos/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteoglicanas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Sítios de Ligação , Configuração de Carboidratos , Glicômica/métodos , Glicosaminoglicanos/metabolismo , Glicosilação , Heparina/análogos & derivados , Heparina/biossíntese , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Proteoglicanas/biossíntese , Proteoglicanas/química , Proteômica/métodos , Relação Estrutura-AtividadeRESUMO
The interaction of chemokines and GAGs (glycosaminoglycans) on endothelial surfaces is a crucial step for establishing a chemotactic gradient which leads to the functional presentation of chemokines to their GPCRs (G-protein-coupled receptors) and thus to activation of approaching leucocytes. Based on molecular modelling, biophysical investigations, cell-based and in vivo experiments, we have developed a novel concept for therapeutically interfering with chemokine-GAG interactions, namely dominant-negative chemokine mutants with improved GAG binding affinity and knocked-out GPCR activity. These recombinant proteins displace their wild-type chemokine counterparts from the natural proteoglycan co-receptors without being able to activate leucocytes via GPCRs. Our mutant chemokines therefore represent the first protein-based GAG antagonists with high therapeutic potential in inflammatory diseases.