NHMRC ECFellow(Peter Doherty Biomedical): Design and evaluation of inhibitors targeting serine proteases in blood to alleviate systemic inflammatory response to coronary artery bypass graft surgery (2014–2018)
Abstract:
Over 20,000 Australians also undergo bypass surgery each year with a 3% mortality rate linked to post-operative
complications. This surgery is, for the great majority of patients, associated with some degree of systemic inflammatory response syndrome (SIRS), which is characterized by fever of non-infectious origin, pathological hypotension, systemic intravascular coagulation, tissue edema, tissue damage and multiple organ failure. The primary cause of SIRS is the contact between the blood tissue and the artificial surface of the
cardiopulmonary bypass machine resulting in activation of the coagulation, fibrinolytic and complement systems, as well as production of inflammatory cytokines by white blood cells. Activation of these pathways are through cascades of serine proteases, which rapidly amplify the initial response.
Since SIRS is a serine protease driven condition, serine protease inhibitors provide a means by which to reduce or prevent SIRS. This research proposal aims at developing potent and selective peptide inhibitors of serine proteases implicated in SIRS, including factor XIIa, plasma kallikrein, factor Xa, tissue factor, factor VIIa and plasmin. Inhibitors will be designed using plant derived inhibitor scaffolds, synthesized, structure characterised and evaluated in silico, in vitro and in vivo.
The outcomes from this proposal will further our understanding of protease-inhibitor interactions and provide invaluable research tools to
advance our understanding of the etiology of SIRS. Lead compounds produced during this research may translate into the clinic, reduce the
morbidity and mortality from complications of artery bypass graft surgery, minimize patient suffering, and also provide a future revenue stream
to The University of Queensland and Australia.
