Proteinase-activated receptor 4 (PAR4): a potential therapeutic target for the inhibition of thrombin-mediated cardiovasular activity

Project: Research - no external fundingResearch (No External Funding)

Description

Thrombin is a potent serine protease involved in regulating haemostasis and thrombosis during vascular injury. In response to vessel damage, release of thrombin into the circulation irreversibly activates a family of GPCRs called proteinase-activated receptors (PARs). PARs are expressed at the surface of platelets and in cells of the vessel wall (endothelial cells and smooth muscle cells - SMCs) where they promote platelet aggregation, endothelial angiogenesis, and SMC migration and proliferation respectively. Thrombin-mediated platelet activation and vascular inflammation occurs via PAR1 and PAR4, which make these receptors attractive therapeutic targets. The competitive PAR1 antagonist, Vorapaxar, has recently been FDA approved in the treatment of a limited cohort of patients suffering recurrent acute coronary syndromes (ACS). However, use of Vorapaxar has been restricted due to severity of bleeding resulting in the elevated risk of associated cerebral haemorrhage. It is clear that subtle approaches are required to combat the bleeding associated with antiplatelet therapies that target the thrombin pathway.

The hypothesis that this proposal is based upon is that targeting the thrombin/PAR4 axis and leaving thrombin/PAR1 activation intact is more effective in treating thrombosis and preserving haemostasis.

Project aim
The key aims are to understand the structure-function relationship of PAR4 and screen novel peptide-mimetic PAR4 modulators to assess their ability to:

i) Inhibit platelet activity
ii) Protect against thrombin-mediated vascular remodelling
Short titleNovel PAR4 biased ligands
StatusFinished
Effective start/end date1/10/1831/05/19

Keywords

  • PAR4
  • GPCR
  • Cardiovascular
  • Biased Ligands