compstatin and Autoimmune-Diseases

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.

Topics: Animals; Autoimmune Diseases; Cell Line, Tumor; Complement Activation; Complement Inactivating Agents; Complement System Proteins; Humans

Therapeutic modulation of complement activation is considered as a promising approach for the treatment of host tissue damage in several inflammatory and autoimmune diseases. Complement component protein C3 is a particularly attractive drug target for complement inhibitors, due to its central role in three pathways of complement activation cascade. Areas covered: The author provides a comprehensive review on compstatin family peptides which have been discovered and optimized as potent and selective C3 inhibitors via a combination of chemical, biophysical and computational approaches. New generations of the compstatin family with improved potency and therapeutic properties have been developed in recent years. Over two decades, compstatin demonstrated therapeutic potential as a first-of-its-kind complement inhibitor in a series of disease models, with encouraging efforts in clinical trials. Expert opinion: Compstatin holds promise for new therapeutic implications in blocking the effect of the complement cascade in a variety of disease conditions. The development of cost-effective treatment options with suitable dosing route and schedule will be critical for patients with complement mediated chronic diseases.

Topics: Animals; Autoimmune Diseases; Complement Activation; Complement C3; Complement Inactivating Agents; Cost-Benefit Analysis; Drug Administration Schedule; Drug Development; Humans; Inflammation; Peptides, Cyclic