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Molecules ; 27(20)2022 Oct 18.
Article in English | MEDLINE | ID: covidwho-2081847


Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from -3.34 to -5.61 kcal mol-1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.

COVID-19 , Polyketides , Mice , Humans , Rats , Animals , Griseofulvin/pharmacology , Antifungal Agents/pharmacology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus , Keratins/metabolism , RNA-Dependent RNA Polymerase
Int J Mol Sci ; 23(13)2022 Jun 21.
Article in English | MEDLINE | ID: covidwho-1963997


Treatment options for Coronavirus Disease 2019 (COVID-19) remain limited, and the option of repurposing approved drugs with promising medicinal properties is of increasing interest in therapeutic approaches to COVID-19. Using computational approaches, we examined griseofulvin and its derivatives against four key anti-SARS-CoV-2 targets: main protease, RdRp, spike protein receptor-binding domain (RBD), and human host angiotensin-converting enzyme 2 (ACE2). Molecular docking analysis revealed that griseofulvin (CID 441140) has the highest docking score (-6.8 kcal/mol) with main protease of SARS-CoV-2. Moreover, griseofulvin derivative M9 (CID 144564153) proved the most potent inhibitor with -9.49 kcal/mol, followed by A3 (CID 46844082) with -8.44 kcal/mol against M protease and ACE2, respectively. Additionally, H bond analysis revealed that compound A3 formed the highest number of hydrogen bonds, indicating the strongest inhibitory efficacy against ACE2. Further, molecular dynamics (MD) simulation analysis revealed that griseofulvin and these derivatives are structurally stable. These findings suggest that griseofulvin and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection.

COVID-19 Drug Treatment , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Griseofulvin/pharmacology , Griseofulvin/therapeutic use , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
Arch Toxicol ; 94(12): 4037-4041, 2020 12.
Article in English | MEDLINE | ID: covidwho-716276


Besides lung drastic involvement, SARS-CoV-2 severely affected other systems including liver. Emerging epidemiological studies brought the attentions towards liver injury and impairment as a potential outcome of COVID19. Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease (TMPRSS2) are the main cell entry receptors of SARS-CoV-2. We have tested the ability of medications to regulate expression of SARS-CoV-2 receptors. Understanding that may reflect how such medications may affect the level of infectivity and permissibility of the liver following COVID-19. Using transcriptomic datasets, Toxicogenomic Project-Genomics Assisted Toxicity Evaluation System (Open TG-GATEs) and GSE30351, we have tested the ability of ninety common medications to regulate COVID-19 receptors expression in human primary hepatocytes. Most medications displayed a dose-dependent change in expression of receptors which could hint at a potentially more pronounced change with chronic use. The expression level of TMPRSS2 was increased noticeably with a number of medications such as metformin. Within the analgesics, acetaminophen revealed a dose-dependent reduction in expression of ACE2, while non-steroidal anti-inflammatory drugs had mixed effect on receptors expression. To confirm the observed effects on primary human hepatocytes, rat hepatocyte treatments data was obtained from DrugMatrix toxicogenomic database (GSE57805), which showed a similar ACE2 and TMPRSS2 expression pattern. Treatment of common co-morbidities often require chronic use of multiple medications, which may result in an additive increase in the expression of ACE2 and TMPRSS2. More research is needed to determine the effect of different medications on COVID-19 receptors.

Betacoronavirus/pathogenicity , Hepatocytes/drug effects , Hepatocytes/virology , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases/genetics , Virus Internalization/drug effects , Acetaminophen/administration & dosage , Acetaminophen/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Cells, Cultured , Coronavirus Infections/therapy , Dose-Response Relationship, Drug , Griseofulvin/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Hypoglycemic Agents/pharmacology , Liver/cytology , Liver/virology , Pandemics , Pneumonia, Viral/therapy , Rats , SARS-CoV-2