C8α Inhibitors

Chemical inhibitors of C8α function by interfering with the complement cascade at various strategic points, effectively hindering the protein's participation in the membrane attack complex (MAC). Eculizumab, by binding to C5, prevents its cleavage into C5a and C5b, a pivotal step required for the MAC formation that recruits C8α. Compstatin follows a similar logic but acts earlier in the pathway; it prevents the cleavage of C3, thereby stalling the sequence of events that would lead to the activation and assembly of the C5b-8 complex necessary for C8α's incorporation into the MAC. PMX205 and Avacopan are both antagonists of the C5a receptor, which by blocking downstream signaling, indirectly prevent the recruitment and functional activity of C8α in the MAC. Nafamostat mesylate, leveraging its broad-spectrum serine protease inhibition, blocks the formation of the C5 convertase, which is critical for the cleavage of C5 and consequently for the recruitment of C8α.

Further along this line of inhibition, K76 COOH and ARC1905 inhibit the formation and function of the C5 convertase complex, again preventing the cleavage of C5 and the subsequent recruitment of C8α to the MAC. Benzylamine, through its activity as a serine protease inhibitor, can indirectly prevent the assembly of the C5b-8 complex that recruits C8α, by inhibiting the proteases involved in the cleavage of C5. Ecallantide targets kallikrein, another protease in the complement activation pathway, which, if inhibited, would impede the cleavage of C5 and thus the engagement of C8α in the MAC. Cyclosporin A has an indirect effect by binding cyclophilin, which is associated with the inhibition of the C3 convertase, and subsequent downstream effects that include the prevention of C8α recruitment to the forming MAC. Lastly, Andrographolide targets the NF-κB pathway, which is involved in the regulation of complement factor transcription. By inhibiting this pathway, the cleavage of C5 is reduced, which in turn indirectly inhibits the recruitment of C8α to the MAC, highlighting a unique approach by targeting regulatory transcription factors upstream of the complement activation cascade.