Chemical Approaches to Modulating Complement-Mediated Diseases

Abstract

Numerous diseases are driven by chronic inflammation, placing major burdens on our health systems. Controlling inflammation is an important preventative and therapeutic goal. Over 40 "Complement" proteins are produced in blood or on cell surfaces through activation of the Complement protein network mainly by infection or injury. These proteins complement immune cells and antibodies to identify, tag, destroy, and eliminate pathogens and infected or damaged cells and repair tissues. If the inflammatory stimulus is not removed by localized acute immune responses, Complement activation may be prolonged or misdirected to healthy cells, and chronic inflammation can lead to inflammatory or autoimmune diseases. The formation, structures, and interplay between Complement proteins are complex, and this has limited our detailed understanding of their roles and importance in physiology and disease. With the availability of new structures for Complement proteins, new knowledge of how they function, and new modulators of Complement-driven signaling, there are also new opportunities to intervene in Complement-mediated disease. Small molecule and peptide-based drug leads, identified as clues for Complement-directed therapeutic development, are assembled here together with the available evidence for their efficacy in cellular and animal models of human inflammatory disease and in some human clinical conditions.

Potent Thiophene Antagonists of Human Complement C3a Receptor with Anti-Inflammatory Activity

“…8 The development of potent, selective, and bioavailable small-molecule ligands for C3aR could lead to a new therapy for treating inflammation-driven diseases, including respiratory, metabolic, cardiovascular, gastrointestinal, central nervous system (CNS), neurodegenerative diseases, and cancers. 9 We have previously downsized the 77-residue C3a protein to equipotent hexapeptides 10 as well as small-molecule agonists (Figure 1) featuring a heterocyclic constraint, such as oxazole 1 (EC 50 7 nM, Ca 2+ , human monocyte-derived macrophage (HMDM)) 5,11 or imidazole 2 (BR103, EC 50 15 nM, Ca 2+ , HMDM). 12 These agonists were equipotent with, and displayed the same functional properties as, human C3a across multiple reporter and signaling cellular assays.…”

“…Human C3a binds to and activates a discrete G-protein-coupled receptor (C3aR) expressed on innate immune and other cell types. , Activation of this receptor stimulates important immune and metabolic responses and is now believed to play important pathological roles in inflammatory and metabolic diseases , and cancers . The development of potent, selective, and bioavailable small-molecule ligands for C3aR could lead to a new therapy for treating inflammation-driven diseases, including respiratory, metabolic, cardiovascular, gastrointestinal, central nervous system (CNS), neurodegenerative diseases, and cancers …”

Emerging Roles for G-protein Coupled Receptors in Development and Activation of Macrophages

“…The “Complement system” is an ancient and conserved protein network of the immune system that is activated through proteolytic cascades by serine proteases in a highly coordinated and controlled fashion (70). Among complement proteins, complement peptide C3a acts via an inflammatory GPCR to trigger immune cell chemotaxis and/or inflammatory responses (70).…”

“…The “Complement system” is an ancient and conserved protein network of the immune system that is activated through proteolytic cascades by serine proteases in a highly coordinated and controlled fashion (70). Among complement proteins, complement peptide C3a acts via an inflammatory GPCR to trigger immune cell chemotaxis and/or inflammatory responses (70). The complement peptide C3a is one of the key chemoattractants and it specifically mediates chemotactic effects by binding to the C3aR expressed on various immune and non-immune cells such as monocytes, macrophages, mast cells, eosinophils, stem cells, and many others.…”

“…Cleavage of complement protein C5 produces complement peptide C5a (70). Similar to C3a, complement peptide C5a is a potent proinflammatory, and chemotactic factor that also acts via an inflammatory GPCR to trigger immune cell activation (71).…”