Investigation of Peptide Binding to Fibrin for the Design of Targeted Molecular Imaging Agents

Fibrin is a major component in early adhesion formation and, consequently, is an attractive molecular target for imaging agents. While previous studies have indicated that the peptide CREKA (Cys-Arg-Glu-Lys-Ala) can bind to fibrin and direct an attached imaging agent to the desired tissue, the molecular mechanism by which CREKA targets fibrin remains unknown. This study aims to determine the binding mode of peptides capable of interacting with fibrin for tissue targeting. Existing fibrin and fibrinogen structures were analyzed, and computational mapping was performed to identify binding hot spots on the surface of the fibrin protein. Models of the binding mode of the potential fibrin targeting peptide, CREKA and its analogs, were developed. The models indicate that the peptides bind in the "A" and "B" holes of fibrin, and therefore, peptide binding would be expected to limit fibrin polymerization. Dynamic light scattering shows that the effects of the peptides on fibrin polymerization are consistent with the modeling. Our findings provide detailed molecular models of peptide-fibrin binders as starting points for the development of optimized peptides for tissue targeting. This study lays the groundwork for the development of targeted contrast agents for the detection of forming adhesions and could be applied more broadly in scenarios such as thrombosis and stroke, where targeting fibrin is also desired.