Although antibodies may be considered the archetype of site-blocking compounds, smaller molecules such as peptides, nucleotides and synthetic molecules may also have the potential to interrupt protein functions by steric hindrance or the induction of conformational changes. Small functional inhibitors of complement activity are expected to have drug-like properties with enhanced pharmacokinetic profiles. These advantages may make them suitable for drug development efforts related to oral bioavailability and better administration routes.
Compstatin is the most developed candidate in this class of substances and recently entered clinical trials. It effectively prevents the cleavage of C3 to its active fragments C3a and C3b and therefore inhibits the most central step in the complement cascade. Although the exact mechanism of compstatin's inhibitory action has not yet been resolved, the recent publication of the cocrystal structure between compstatin and C3c suggests that a disruption of protein-protein interactions during convertase formation may be an important determinant. This finding has led to the hypothesis that a conformational change or an interruption in protein-protein interactions is responsible for its activity. Compstatin has shown effective complement inhibition in a variety of experimental disease models. Despite a narrow selectivity for primate C3 that may affect preclinical animal experiments, its high efficacy and rather small size make it a promising drug candidate. Its inhibitory efficacy has been increased by 264-fold through the use of rational and combinatorial synthesis, structural analysis, and computational approaches to identify active analogs.
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