Cell-Penetrating Pepducin Therapy Targeting PAR1 in Supjects with Coronary Artery Disease

Paul A. Gurbel, Kevin P. Bliden, Susan E. Turner, Udaya S. Tantry, Martin G. Gesheff, Travis P. Barr, Lidija Covic, Athan Kuliopulos

Research output: Contribution to journalArticlepeer-review


Objective-Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report the first human use of a protease-activated receptor-1-based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications of percutaneous coronary interventions. Approach and Results-PZ-128 was administered by 1 to 2 hours continuous intravenous infusion (0.01-2 mg/kg) to 31 supjects with coronary artery disease or multiple coronary artery disease risk factors. Safety, antiplatelet efficacy, and pharmacokinetics were assessed at baseline and 0.5, 1, 2, 6, 24 hours, and 7 to 10 days postdosing. The inhibitory effects of PZ-128 on platelet aggregation stimulated by the protease-activated receptor-1 agonist SFLLRN (8 μmol/L) at 30 minutes to 6 hours were dose dependent with 20% to 40% inhibition at 0.3 mg/kg, 40% to 60% at 0.5 mg/kg, and ≥80% to 100% at 1 to 2 mg/kg. The supgroup receiving aspirin in the 0.5 and 1-mg/kg dose cohorts had 65% to 100% inhibition of final aggregation to SFLLRN at 30 minutes to 2 hours and 95% to 100% inhibition by 6 hours. The inhibitory effects of 0.5 mg/kg PZ-128 were reversible with 50% recovery of aggregation to SFLLRN by 24 hours. There were no significant effects of PZ-128 on aggregation induced by AYPGKF, ADP, or collagen, indicating that the observed effects were specific to protease-activated receptor-1. The plasma half-life was 1.3 to 1.8 hours, and PZ-128 was nondetectable in urine. There were no effects on bleeding, coagulation, clinical chemistry, or ECG parameters. Conclusions-PZ-128 is a promising antiplatelet agent that provides rapid, specific, dose dependent, and reversible inhibition of platelet protease-activated receptor-1 through a novel intracellular mechanism. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01806077.

Original languageEnglish (US)
Pages (from-to)189-197
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number1
StatePublished - Jan 1 2016


  • aspirin
  • collagen
  • coronary artery disease
  • lipopeptides
  • risk factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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