The development of a novel molecule format, referred to as “bicyclic hetero peptidimer” (Figure 1), as a new therapeutic molecule format is the first objective in this project. By combination of a moderate active inhibitor of FXIIa with a FXII binding peptide, we hypothesized that this will increase residence time and overall affinity, leading to a more potent inhibitor. The bicyclic hetero peptidimer should serve as potent FXII inhibitor with high inhibitory activity (picomolar range), be easy accessible to chemical synthesis, and have a long circulation half-life.
Coagulation factor XII (FXII, Hageman factor) is a component of the intrinsic pathway of coagulation and FXII is activated by conversion to FXIIa, which serves as serine protease and cleaves plasma prekallikrein (PPK) to generate active plasma kallikrein (PK) which leads in a release of the high molecular weight kininogen (HK). HK liberates the inflammatory mediator bradykinin (BK), which is the fundament of the autosomal dominantly inherited blood disorder hereditary angioedema (HAE). There are three types of HAE, which all lead to an over stimulated production of bradykinin as a result of an increased activity of FXIIa. The patients suffer episodic attacks of swelling, which can affect skin and mucosa as well as the inner organs. This leads to massive pain and can be life threatening in the case of swelling in the throat. The high inhibitory activity is crucial for this target, where only small amounts of activated FXII protease can start a cascade which amplifies its self. FXII plays also an important role in the activation of the intrinsic coagulation pathway. Activation of FXII on artificial surfaces during cardiopulmonary bypass surgery can lead to excessive coagulation and inflammation. Inhibition of FXIIa during this medical procedure could potentially reduce or even eliminate the undesired effects.
The main goal of our project in the end is the development of a potent inhibitor of the intrinsic coagulation cascade, preferably in the picomolar range for FXIIa inhibition. A further goal is the improvement of pharmacokinetic parameters after the successful identification of a potent bicyclic peptidic inhibitor.
For in vitro and in vivo experiments, corn trypsin inhibitor (CTI, Ki = 24 nM) is available, but this molecule would most likely raise an immune reaction if applied as a therapeutic. FXIIa inhibitory bicyclic peptides developed until recently showed too low inhibitory activity. Small molecule FXIIa inhibitors such as PCK (IC50 = 180 nM) and coumarin-based molecuels have been reported but show weak activities. Monoclonal antibodies inhibiting FXIIa are in development. Neither small molecule FXIIa inhibitors nor FXIIa antibodies have reached the market yet.
