Exploiting fibrin knob:hole interactions for the control of fibrin polymerization

The minimization of blood loss represents a significant clinical need in the arena of surgery, trauma, and emergency response medicine. Fibrinogen is our body's native polymer system activated in response to tissue and vasculature injury, and forms the foundation of the most widely employed surgical sealant and hemostatic agent. Non-covalent knob:hole interactions are central to the assembly of fibrin that leads to network and clot formation. This project exploits these affinity interactions as a strategy to direct fibrin polymerization dynamics and network structure so as to develop a temperature-triggered polymerizing fibrin mixture for surgical applications. Short peptides modeled after fibrin knob sequences have been shown to alter fibrin matrix structure by competing with native fibrin knobs for binding to the available holes on fibrinogen and fibrin. The fusion of such knob peptides to a non-native component should facilitate binding of the fused component to fibrinogen/fibrin, and may permit the concomitant modification of the fibrin matrix. We examined this hypothesis in a three-step approach involving (a) analyzing the ability of tetrapeptide knob sequences to confer fibrin(ogen) affinity on a non-fibrin protein, (b) investigating the effect of knob display architecture on fibrin(ogen) structure, and (c) designing a temperature-responsive knob-displaying construct to modulate fibrin(ogen) affinity at different temperature regimes, thus altering fibrin(ogen) structure.Ph