PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization

Abstract

Objective: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02–0.75); P =0.02. Conclusions: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02561000.

Lipidated peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as biased allosteric ligands

“…By selectively engaging only a subset of potential intracellular partners, allosteric agonists or biased ligands may offer an unparalleled means to understand and control GPCR-mediated signaling ( 48 ). Over the years, the pepducin concept has yielded numerous allosteric agonists and antagonists for several GPCRs, some of them reaching clinical trials ( 49 , 50 , 51 ). By stabilizing or disrupting molecular interactions that change the energy landscape of a GPCR, pepducins have the potential to affect the conformational ensemble in ways that affect signaling ( 52 ).…”

Membrane-tethered peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as allosteric biased ligands

“…By selectively engaging only a subset of potential intracellular partners, allosteric agonists or biased ligands may offer an unparalleled means to understand and control GPCR-mediated signaling (46). Over the years, the pepducin concept has yielded numerous allosteric agonists and antagonists for several GPCRs, some of them reaching clinical trials (47-49). By stabilizing or disrupting molecular interactions that change the energy landscape of a GPCR, pepducins have the potential to affect the conformational ensemble in ways that affect signaling (50).…”

Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

“…In phase II trials, patients tolerated PZ-128 (12) well, and an exploratory endpoint measuring major adverse coronary events and myocardial injury showed fewer events in the PZ128 group than in the placebo group (Kuliopulos et al, 2020). Impressively, the palmitate conjugation to an otherwise unmodified heptapeptide produced the bioavailability, metabolic stability, and membrane permeability necessary for intravenous administration in clinical trials of an intracellular target (Figures 3C,11,gray).…”

“…In fact, several peptide/peptidomimetic AMs have entered clinical trials, including PZ-128 at the protease-activated receptor 1 (PAR1) (Kuliopulos et al, 2020) and Vc1.1 at Gamma-aminobutyric acid B receptors (GABA B ), 3,4 highlighting their ability to achieve clinically acceptable drug-like properties. Moreover, the 31-amino acid Semaglutide (MW 4,114)-marketed as Rybelsus ® -is an orally available FDA-approved drug to treat type 2 diabetes (FDA, 2020).…”

“…The attached lipid moiety facilitates membrane insertion followed by "flipping" the peptide across the bilayer to the cytosolic side, improving membrane permeability and peripheral bioavailability [e.g., , Kuliopulos and Covic (2003), Tsuji et al (2013), and Zhang et al (2015)] (Figure 3C). Reported pepducin AMs include P1pal-12 (10), P1pal-i1-11 (11), and p1pal7 (or PZ128) (12) at the PAR1 (; Kuliopulos and Covic, 2003;Leger et al, 2006;Cisowski et al, 2011;Zhang et al, 2012;Gurbel et al, 2016;Kuliopulos et al, 2020); P1pal19 (13), ATI-2341 (14), ATI-2346 (15), PZ218 (16), and PZ210 (17) at CXCR4 (Tchernychev et al, 2010;Janz et al, 2011;O'Callaghan et al, 2012;Quoyer et al, 2013); P4pal-10 (18) at the protease-active receptor 4 (PAR4) (Leger et al, 2006;Carr et al, 2016;Holdfeldt et al, 2020); TAT-h3L4F (19) and r3L4F (20) at the 5HT 2C R (Anastasio et al, 2013;Ji et al, 2006); mF3pal_16 (21) at formyl peptide receptor 3 (FPR3) (Lee et al, 2020); and ICL3-2 (22), ICL1-9 (23), ICL3-8 (24), ICL1-11 (25), and ICL1-4 (26) at the β2-adrenergic receptor (ß 2 AR) (Table 2) (Carr et al, 2014;Grisanti et al, 2018) and even led to 12 entering clinical trials (Kuliopulos et al, 2020).…”