Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1430548

Gestodene, a Novel Positive Allosteric Modulator of PAR1, Enhances PAR1-mediated Human Platelet Aggregation

Provisionally accepted
So-Hyeon Park So-Hyeon Park 1Yunkyung Heo Yunkyung Heo 2Il Kwon Il Kwon 3Hyejin jeon Hyejin jeon 2Yechan LEE Yechan LEE 2Jieun Kim Jieun Kim 4Ji Hoe Heo Ji Hoe Heo 5WAN NAMKUNG WAN NAMKUNG 2*
  • 1 Yonsei University, Seoul, Seoul, Republic of Korea
  • 2 College of Pharmacy, Yonsei University, Seoul, Republic of Korea
  • 3 Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Seoul, Republic of Korea
  • 4 Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea
  • 5 Severance Hospital, College of Medicine, Yonsei University, Seoul, Seoul, Republic of Korea

The final, formatted version of the article will be published soon.

    Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In the present study, we performed a cell-based screening to identify PAMs of PAR1 and found a novel PAM of PAR1, gestodene, an oral contraceptive (OC). Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP-induced morphological changes in the human megakaryoblastic leukemia cell line MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1. Our results demonstrate that gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.

    Keywords: PAR1, PAM, Gestodene, Platelet, Thromboembolism

    Received: 10 May 2024; Accepted: 12 Jul 2024.

    Copyright: © 2024 Park, Heo, Kwon, jeon, LEE, Kim, Heo and NAMKUNG. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: WAN NAMKUNG, College of Pharmacy, Yonsei University, Seoul, Republic of Korea

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.