Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

Abstract Human complement fragment 5a (C5a) is one of the most potent glycoproteins generated downstream of C3a and C4a during late‐stage activation of the complement signaling cascade. C5a recruits receptors like C5aR1 and C5aR2 and is established to play a critical role in complement‐mediated inflammation. Thus, excessive C5a in the plasma due to aberrant activation of the complement contributes to the pathophysiology of several chronic inflammatory diseases. Therefore, restricting the excessive interaction of C5a with its receptors by neutralizing C5a has been one of the most effective therapeutic strategies for the management of inflammatory diseases. Indeed, antibodies targeting C5 (Eculizumab), the precursor of C5a, and C5a (Vilobelimab) have already been approved by the FDA. Still, small designer peptides that work like antibodies and can target and stop C5a from interacting with its receptors seem to be a possible therapeutic alternative to antibodies because they are smaller, cheaper to make, more specific to their target, and can get through membrane barriers. As a proof‐of‐principle, the current study describes the computational design and evaluation of a pair of peptides that are able to form stable high‐affinity complexes with the epitope regions of C5a that are important for the recruitment of C5aR1 and C5aR2. The computational data further supports the potential of designer peptides for mimicking the function of antibodies targeting C5a. However, further experimental studies will be required to establish the structure–function relationship of the designer peptides and also to establish the hypothesis of antibody‐like peptides targeting C5a.