Inhibition of the Serine Proteases of the Complement System

Abstract

Proteases play important roles in human physiology and pathology. The complement system is a proteolytic cascade, where serine proteases activate each other by limited proteolysis in a strictly ordered manner. Serine proteases are essential in both the initiation and the amplification of the cascade. Since uncontrolled complement activation contributes to the development of serious disease conditions, inhibition of the complement serine proteases could be an attractive therapeutic approach. In this chapter, we give a brief overview of the major types of natural serine protease inhibitors and their role in controlling the complement cascade. A special emphasis is laid on C1-inhibitor, a natural complement protease inhibitor, which is approved for clinical use in hereditary angioedema (HAE). We also examine the potential of developing artificial complement protease inhibitors. Synthetic small-molecule drugs can be very efficient serine protease inhibitors, but they usually lack sufficient specificity. A promising approach to yield more specific compounds is the alteration of natural protease inhibitors through engineering or directed evolution resulting in new variants with fine-tuned specificity and enhanced affinity.

Iripin-3, a New Salivary Protein Isolated From Ixodes ricinus Ticks, Displays Immunomodulatory and Anti-Hemostatic Properties In Vitro

“…Serpins are particularly intriguing to study, not only due to their unique trapping inhibitory mechanism but also because they regulate a variety of physiological processes in many organisms. The functional diversity of the serpin superfamily is exemplified by the widely studied human serpins, which have been shown to regulate blood pressure, transport hormones, and control blood coagulation, fibrinolysis, angiogenesis, programmed cell death, inflammation, or complement activation (81)(82)(83)(84). We presume that ticks employ some of their serpins to modulate host defenses, as evidenced by several tick serpins with anti-platelet, anti-coagulant, anti-inflammatory, and/or immunomodulatory properties that have been shown to be secreted via saliva into the host (34)(35)(36)(37)72).…”

Cathepsins: Proteases that are vital for survival but can also be fatal

“…Its homologs or analogs include other serine proteases such as trypsin, thrombin, subtilisin, chymotrypsin, elastase, collagenase, and kallikrein. Together they control digestion, blood coagulation, immune regulation, protein metabolism, autophagy and apoptosis, among numerous other functions [5,[117][118][119]. Apart from the autocatalysis of cathepsins, these proteases play role in the activation of cathepsins.…”

Complement, a target for therapy in inflammatory and degenerative diseases

“…In some diseases these barriers become damaged and leaky with disease progression, but it is likely that complement activation contributes to the early, pre-inflammatory stages of eye and brain diseases, so to be of value complement --inhibiting drugs are required in the relevant organ early in the disease when the barriers are still intact. Assuming that they have good bioavailability, small-molecule drugs may have advantages over biologics in these contexts because of their higher tissue penetrance; however, of the numerous small-molecule anti-complement agents that have been developed and tested in humans, none has yet progressed to the market [39][40][41] .…”