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

Autor:	Carmo HRP; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Castillo AR; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Bonilha I; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Gomes EIL; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Barreto J; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Moura FA; Brigham and Women's Hospital, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.; TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States., Davanzo GG; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., de Brito Monteiro L; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Muraro SP; Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Fabiano de Souza G; Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Morari J; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil., Galdino FE; Institute of Chemistry, University of Campinas (UNICAMP), Campinas, Brazil.; Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil., Brunetti NS; Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Reis-de-Oliveira G; Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Carregari VC; Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil., Nadruz W; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil., Martins-de-Souza D; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil.; Laboratory of Neuroproteomics, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.; D'Or Institute for Research and Education (IDOR), São Paulo, Brazil.; Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil., Farias AS; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil.; Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.; Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil., Velloso LA; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil., Proenca-Modena JL; Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.; Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil., Mori MA; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil.; Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil.; Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, Brazil., Loh W; Institute of Chemistry, University of Campinas (UNICAMP), Campinas, Brazil., Bhatt DL; Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, United States., Yellon DM; The Hatter Cardiovascular Institute, University College London, London, United Kingdom., Davidson SM; The Hatter Cardiovascular Institute, University College London, London, United Kingdom., De Oliveira PG; Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.; Sport Traumatology Group, Department of Orthopaedics and Traumatology, Santa Casa de São Paulo School of Medical Sciences, São Paulo, Brazil., Moraes-Vieira PM; Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.; Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, Brazil.; Experimental Medicine Research Cluster (EMRC), University of Campinas (UNICAMP), Campinas, Brazil., Sposito AC; Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (UNICAMP), Campinas, Brazil.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Oct 07; Vol. 15, pp. 1402032. Date of Electronic Publication: 2024 Oct 07 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1402032
Abstrakt:	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. Competing Interests: DB discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hô pitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and United States national co-leader, funded by Bayer), WebMD (CME steering committees), (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women' s Hospital who assigned to Lexicon; neither I nor Brigham and Women' s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. AS discloses the following relationships - Research Funding: Amgen, AstraZeneca, National Council for Scientific and Technological Development (CNPq) and Fundaç and#227; o de Apoio and#224; Pesquisa do Estado de Sã o Paulo (FAPESP). Dr. Pedro Gonç alves de Oliveira is responsible for R&D activities at TRB Pharma Indú stria Quí mica e Farmace utica Ltda, SP, Brazil. TRB Pharma is the owner of the product ARTRODAR® a diacerein-based product for osteoarthritis treatment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (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.)
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