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

Helison R P Carmo; Alejandro Rossel Castillo; Isabella Bonilha; Erica I L Gomes; Joaquim Barreto; Filipe A Moura; Gustavo Gastão Davanzo; Lauar de Brito Monteiro; Stéfanie Primon Muraro; Gabriela Fabiano de Souza; Joseane Morari; Flávia Elisa Galdino; Natália S Brunetti; Guilherme Reis-de-Oliveira; Victor Corasolla Carregari; Wilson Nadruz; Daniel Martins-de-Souza; Alessandro S Farias; Licio A Velloso; José Luiz Proenca-Modena; Marcelo A Mori; Watson Loh; Deepak L Bhatt; Derek M Yellon; Sean M Davidson; Pedro G De Oliveira; Pedro M Moraes-Vieira; Andrei C Sposito

doi:10.3389/fphar.2024.1402032

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

Front Pharmacol. 2024 Oct 7:15:1402032. doi: 10.3389/fphar.2024.1402032. eCollection 2024.

Authors

Helison R P Carmo^#¹, Alejandro Rossel Castillo^#¹, Isabella Bonilha¹, Erica I L Gomes¹, Joaquim Barreto¹, Filipe A Moura^{2

3}, Gustavo Gastão Davanzo⁴, Lauar de Brito Monteiro⁴, Stéfanie Primon Muraro⁵, Gabriela Fabiano de Souza⁵, Joseane Morari⁶, Flávia Elisa Galdino^{7

8}, Natália S Brunetti⁹, Guilherme Reis-de-Oliveira¹⁰, Victor Corasolla Carregari¹⁰, Wilson Nadruz¹, Daniel Martins-de-Souza^{6

10

11

12}, Alessandro S Farias^{6

9

12}, Licio A Velloso⁶, José Luiz Proenca-Modena^{5

12}, Marcelo A Mori^{6

12

13}, Watson Loh⁷, Deepak L Bhatt¹⁴, Derek M Yellon¹⁵, Sean M Davidson¹⁵, Pedro G De Oliveira^{16

17}, Pedro M Moraes-Vieira^{4

6

12}, Andrei C Sposito¹

Affiliations

¹ Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil.
² Brigham and Women's Hospital, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
³ TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
⁴ Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
⁵ Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
⁶ Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil.
⁷ Institute of Chemistry, University of Campinas (UNICAMP), Campinas, Brazil.
⁸ Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.
⁹ Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
¹⁰ Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
¹¹ D'Or Institute for Research and Education (IDOR), São Paulo, Brazil.
¹² Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil.
¹³ Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil.
¹⁴ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
¹⁵ The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
¹⁶ Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
¹⁷ Sport Traumatology Group, Department of Orthopaedics and Traumatology, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil.

^# Contributed equally.

Abstract

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 h 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 3CL^pro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PL^pro) 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; clinical trial; diacerein; pre-clinical; rhein.

Copyright © 2024 Carmo, Castillo, Bonilha, Gomes, Barreto, Moura, Davanzo, de Brito Monteiro, Muraro, Fabiano de Souza, Morari, Galdino, Brunetti, Reis-de-Oliveira, Carregari, Nadruz, Martins-de-Souza, Farias, Velloso, Proenca-Modena, Mori, Loh, Bhatt, Yellon, Davidson, De Oliveira, Moraes-Vieira and Sposito.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Funding for this study was provided by grants from the Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP, grant number: 2020/05430-7 to ACS, 2020/04558-0 to JLPM, 2018/17792-0 to HRPC, and 2020/12649-5 to ARC). This study was also supported by Fundo de Apoio ao Ensino, Pesquisa e Extensão of UNICAMP (FAEPEX-UNICAMP, grant number: 2391/20 to ACS; and 2266/20 to JLPM). National Council for Scientific and Technological Development (CNPq) supported (grant number: 304257/2021-4 to AS, and 305628/2020-8 to JP-M). In addition, TRB PHARMA’s support in donating diacerein and placebo capsules.