Bioactive peptides for therapeutic applications in cardiovascular disease

Abstract

Cardiovascular diseases including stroke are the leading cause of death and disability worldwide. The underlying pathology for most of these conditions is thrombosis, which is mediated by the coagulation cascade. Despite a wealth of clinically approved anticoagulants that target this pathway, there are currently no treatment options that provide the ideal safety and efficacy profile, with many imparting severe bleeding side effects. Furthermore, there are no approved therapeutics to treat the severe neuronal damage that occurs after stroke. Given the urgent need for novel and effective drugs to treat cardiovascular disease, several important therapeutic targets have emerged including Coagulation Factor XIIa (FXIIa) Thrombin, and Acid Sensing Ion Channel 1a (ASIC1a). As such, this thesis describes efforts towards the development of novel peptidic drugs that inhibit these important proteins. The identification, synthesis and optimisation of potent and selective cyclic peptide inhibitors of FXIIa that were discovered by Random Non-Standard Integrated Peptide Discovery (RaPID) mRNA display technology is initially described. Additionally, this thesis outlines efforts towards the synthesis of two arthropod derived molecules with clinically interesting biological activity: Thrombostasin, from the horn fly Haematobia irritans and Hi1a from K’Gari funnel web spider Hadronyche infensa.