Integrating Innate Immunity into a Global “Systems” Context: The Complement Paradigm Shift - Systems Biology: Networks, Models, and Applications - page 173

technique makes it a suitable method for the study of the multiplicity of
interactions of complement components within the complement
system and with other serum or membrane-bound proteins.
Hydrogen/deuterium exchange coupled to mass spectrometry has
recently been used to probe the conformational changes of the C3 mol-
ecule in its transition from native to hydrolyzed state [21], and it is
becoming clear that such a methodology could provide valuable
insight into the structural determinants that govern the interaction of
C3 with various ligands and receptors (e.g., C3d/CR2).
Rational and Combinatorial Design of Complement Inhibitors:
The Case of Compstatin
Complement has been primarily associated with the propagation of
proinflammatory responses in the context of human disease.
Complement activation has been implicated in the induction of acute
inflammatory reactions leading to complications such as acute graft
rejection, local tissue injury, and multiple organ failure [22]. Bedside
therapies that target these harmful proinflammatory properties of com-
plement activation are not yet available and considerable effort has
been devoted in recent years to the development of effective drugs that
inhibit complement activation. Complement inhibitors that are cur-
rently under development include small-size organic compounds,
synthetic peptides, and also large monoclonal antibodies [23,24]. Our
laboratory has focused its research efforts on the discovery of comple-
ment inhibitors that bind to complement component C3. Potential
C3-binding inhibitors are considered a more effective means of block-
ing complement activation since all complement pathways converge to
the cleavage and activation of C3.
High-throughput combinatorial screening strategies have been
employed in conjunction with fine structural and computational
approaches for the identification and subsequent optimization of
potential C3-binding inhibitors. The screening of a phage-displayed
random peptide library led to the identification of a 27-residue peptide
that binds to C3 and inhibits complement activation [25]. This peptide
was truncated to a 13-residue cyclic species that maintained complete
activity, and was hereafter named compstatin . Compstatin blocks com-
plement activation by preventing the C3 convertase-dependent
proteolytic cleavage of C3 and the release of its bioactive fragments,
C3b and the anaphylatoxin C3a. The activity of compstatin has been
successfully tested in a series of in vitro, in vivo, ex vivo, and in
vivo/ex vivo interface studies [25-34]. Compstatin constitutes an ideal
lead compound for drug development because of its low toxicity
in vivo and its small size, which allows for rapid, cost-effective, and
large-scale synthesis.