Abstract
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.
Keywords: SARS-CoV-2; dermatophytic fungi; drug repurposing; griseofulvin; griseofulvin derivatives; gsf gene cluster; polyketide compound; spindle microtubule.
【저자키워드】 Drug repurposing, SARS-CoV-2, griseofulvin, griseofulvin derivatives, spindle microtubule., polyketide compound, gsf gene cluster, dermatophytic fungi, 【초록키워드】 ACE2, severity, SARS-CoV-2 main protease, Spike protein, Replication, infections, Hepatitis, RBD, viral replication, hepatitis C virus, Liver injury, RdRP, RNA-dependent RNA polymerase, metabolites, information, rodent, mechanism, metabolite, binding, Inhibitory effects, Interaction, Vascular, FDA-approved drug, SARS-CoV-2 entry, domain, inhibitory effect, therapeutic interventions, molecular docking analysis, derivative, mitosis, ascomycetes, hepatocyte, Cell, ENhance, IMPROVE, produced, responsible, addition, treated, introduced, contribute, multifunctional, explain, disrupt, cancer cell, capillary blood flow, filament protein, K18, Mallory, 【제목키워드】 current,