Frontiers in Pharmacology (Oct 2024)
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,
- Filipe A. Moura,
- Gustavo Gastão Davanzo,
- Lauar de Brito Monteiro,
- Stéfanie Primon Muraro,
- Gabriela Fabiano de Souza,
- Joseane Morari,
- Flávia Elisa Galdino,
- Flávia Elisa Galdino,
- Natália S. Brunetti,
- Guilherme Reis-de-Oliveira,
- Victor Corasolla Carregari,
- Wilson Nadruz,
- Daniel Martins-de-Souza,
- Daniel Martins-de-Souza,
- Daniel Martins-de-Souza,
- Daniel Martins-de-Souza,
- Alessandro S. Farias,
- Alessandro S. Farias,
- Alessandro S. Farias,
- Licio A. Velloso,
- José Luiz Proenca-Modena,
- José Luiz Proenca-Modena,
- Marcelo A. Mori,
- Marcelo A. Mori,
- Marcelo A. Mori,
- Watson Loh,
- Deepak L. Bhatt,
- Derek M. Yellon,
- Sean M. Davidson,
- Pedro G. De Oliveira,
- Pedro G. De Oliveira,
- Pedro M. Moraes-Vieira,
- Pedro M. Moraes-Vieira,
- Pedro M. Moraes-Vieira,
- Andrei C. Sposito
Affiliations
- Helison R. P. Carmo
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Alejandro Rossel Castillo
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Isabella Bonilha
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Erica I. L. Gomes
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Joaquim Barreto
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Filipe A. Moura
- Brigham and Women’s Hospital, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Filipe A. Moura
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Gustavo Gastão Davanzo
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Lauar de Brito Monteiro
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Stéfanie Primon Muraro
- Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Gabriela Fabiano de Souza
- Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Joseane Morari
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- Flávia Elisa Galdino
- Institute of Chemistry, University of Campinas (UNICAMP), Campinas, Brazil
- Flávia Elisa Galdino
- Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
- Natália S. Brunetti
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Guilherme Reis-de-Oliveira
- 0Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Victor Corasolla Carregari
- 0Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Wilson Nadruz
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- Daniel Martins-de-Souza
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- Daniel Martins-de-Souza
- 0Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Daniel Martins-de-Souza
- 1D’Or Institute for Research and Education (IDOR), São Paulo, Brazil
- Daniel Martins-de-Souza
- 2Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil
- Alessandro S. Farias
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- Alessandro S. Farias
- Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Alessandro S. Farias
- 2Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil
- Licio A. Velloso
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- José Luiz Proenca-Modena
- Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- José Luiz Proenca-Modena
- 2Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil
- Marcelo A. Mori
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- Marcelo A. Mori
- 2Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil
- Marcelo A. Mori
- 3Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil
- Watson Loh
- Institute of Chemistry, University of Campinas (UNICAMP), Campinas, Brazil
- Deepak L. Bhatt
- 4Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- Derek M. Yellon
- 5The Hatter Cardiovascular Institute, University College London, London, United Kingdom
- Sean M. Davidson
- 5The Hatter Cardiovascular Institute, University College London, London, United Kingdom
- Pedro G. De Oliveira
- 6Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
- Pedro G. De Oliveira
- 7Sport Traumatology Group, Department of Orthopaedics and Traumatology, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil
- Pedro M. Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Pedro M. Moraes-Vieira
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil
- Pedro M. Moraes-Vieira
- 2Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil
- Andrei C. Sposito
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil
- DOI
- https://doi.org/10.3389/fphar.2024.1402032
- Journal volume & issue
-
Vol. 15
Abstract
BackgroundSevere 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.MethodsHuman 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).ResultsIn 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).ConclusionThe 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.
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