C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation.
Complement activation is initiated by the pattern-recognition molecules complement component C1q, mannose-binding lectin (MBL) and ficolins (H-, L-, M-ficolin), which typically recognize antibody-antigen complexes or foreign polysaccharides. The associated proteases (C1r, C1s, MASP-1 and MASP-2) then activate the complement system. The serpin C1-inhibitor (C1-inh) blocks activity of all these complexes and has been successfully used in models of disease. Many structures of these components became available recently, including that of C1-inh, facilitating the structure-guided design of drugs targeting complement activation. Here, we propose an approach in which therapeutic proteins are made up of natural protein domains and C1-inh to allow targeting to the site of inflammation and more specific inhibition of complement activation. In particular, engineering a fast-acting C1-inh or fusing it to an 'aiming module' has been shown to be feasible and economical using a humanized yeast expression system. Complement-mediated inflammation has been linked to ischemia-reperfusion injury, organ graft rejection and even neurodegeneration, so targeting this process has direct clinical implications.
Beinrohr
László
L
Institute of Enzymology, Karolina út 29, H-1113 Budapest, Hungary. lbeinrohr@enzim.hu
Dobó
József
J
Závodszky
Péter
P
Gál
Péter
P
D000818:Animals; D003167:Complement Activation / Q000187:drug effects* / Q000502:physiology; D003172:Complement C1 / Q000502:physiology; D050718:Complement C1 Inhibitor Protein / Q000502:physiology; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D037601:Mannose-Binding Lectin / Q000502:physiology; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000502:physiology; D008954:Models, Biological; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000627:therapeutic use
D003172:Complement C1; D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; D037601:Mannose-Binding Lectin; D011994:Recombinant Proteins; D050606:Mannose-Binding Protein-Associated Serine Proteases