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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Translational Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1402032

Diacerein reduces inflammasome activation and SARS-CoV-2 virus replication: a proof-of-concept translational study

Provisionally accepted
Helison R. Carmo Helison R. Carmo 1Alejandro R. Castillo Alejandro R. Castillo 1Isabella Bonilha Isabella Bonilha 1Erica I. Gomes Erica I. Gomes 1Joaquim Barreto Joaquim Barreto 1Filipe A. Moura Filipe A. Moura 2Gustavo G. Davanzo Gustavo G. Davanzo 1Ana Campos Codo Ana Campos Codo 1Lauar Monteiro Lauar Monteiro 1Stéfanie P. Muraro Stéfanie P. Muraro 1Gabriela F. de Souza Gabriela F. de Souza 1Joseane Morari Joseane Morari 1Flávia E. Galdino Flávia E. Galdino 1Natália B. Silva Natália B. Silva 1Guilherme Reis-de-Oliveira Guilherme Reis-de-Oliveira 1Victor C. Carregari Victor C. Carregari 1Wilson Nadruz Wilson Nadruz 1Daniel Martins-de-Souza Daniel Martins-de-Souza 1Alessandro S. Farias Alessandro S. Farias 1Licio A. Velloso Licio A. Velloso 1José Luiz Proença-Modena José Luiz Proença-Modena 1Marcelo A. Mori Marcelo A. Mori 1Watson Loh Watson Loh 1Deepak L. Bhatt Deepak L. Bhatt 3Derek Yellon Derek Yellon 4Sean M. Davidson Sean M. Davidson 4Pedro G. de Oliveira Pedro G. de Oliveira 5Pedro Vieira Pedro Vieira 1Andrei C. Sposito Andrei C. Sposito 1*
  • 1 State University of Campinas, Campinas, São Paulo, Brazil
  • 2 Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • 3 Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • 4 University College London, London, England, United Kingdom
  • 5 University of São Paulo, São Paulo, Rio Grande do Sul, Brazil

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

    Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection. Methods: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n=7) or placebo (n=7) therapies every 12 hours for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D). Results: In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1β secretion caused by SARS-CoV-2 infection in human PBMCs (p<0.05), and suppressed viral replication when administered either before or after the virus incubation (p<0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CLpro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PLpro) virus and in the phosphorylation of proteins related cytoskeleton network (p<0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo (p<0.05). Conclusion: The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials.

    Keywords: COVID-19, Diacerein, Rhein, pre-clinical, Clinical Trial

    Received: 16 Mar 2024; Accepted: 06 Sep 2024.

    Copyright: © 2024 Carmo, Castillo, Bonilha, Gomes, Barreto, Moura, Davanzo, Campos Codo, Monteiro, Muraro, de Souza, Morari, Galdino, Silva, Reis-de-Oliveira, Carregari, Nadruz, Martins-de-Souza, Farias, Velloso, Proença-Modena, Mori, Loh, Bhatt, Yellon, Davidson, de Oliveira, Vieira and Sposito. 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: Andrei C. Sposito, State University of Campinas, Campinas, 13083-970, São Paulo, Brazil

    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.