Kevin McKernan先生が、イベルメクチンがSV40に抗ウイルス活性を有していること＆ｐ53遺伝子の変異阻止に関してTweetしている

Ivermectin, a broad-spectrum antiparasitic agent, has demonstrated antiviral properties against various viruses, including Simian Virus 40 (SV40). Its antiviral activity is primarily attributed to the inhibition of the importin a/ẞ1-mediated nuclear import pathway, which many viruses exploit to transport their proteins into the host cell nucleus.

Mechanism of Action:

Inhibition of Nuclear Import: Ivermectin disrupts the importin a/ẞ1 complex, preventing the nuclear import of viral proteins essential for replication. This mechanism has been observed in several viruses, including SV40.

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Research Findings:

SV40 Large T-Antigen (TAg): Studies have shown that ivermectin reduces the nuclear import of SV40 TAg, a protein crucial for viral replication.

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Broad-Spectrum Antiviral Activity: Ivermectin has demonstrated efficacy against various

viruses, including HIV-1 and dengue virus, by targeting the importin a/ẞ-mediated nuclear import pathway.

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Conclusion:

The literature indicates that ivermectin can inhibit SV40 replication by interfering with the nuclear import of viral proteins. This action is part of its broader antiviral capabilities against multiple viruses that rely on the importin a/ẞ1 pathway for replication.

For a more in-depth understanding, you may refer to the following studies:

Inhibition of Human Adenovirus Replication by the Importin a/ẞ1 Inhibitor Ivermectin:

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Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus:

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RESULTS

Ivermectin inhibits HAdV-C5 progeny production in a dose-dependent manner.

Ivermectin has been previously demonstrated to function as an antiviral agent against several viruses that encode factors that rely on host Imp-a/ẞ1-mediated nuclear transport (31). Ivermectin has been described as a general inhibitor of this pathway and was shown to reduce nuclear import of viral proteins such as SV40 large T-antigen (TAg), HIV integrase, DENV NS5, and BKPyV VP2 and VP3 (32-35). To build upon these initial studies, we sought to test this drug's ability to affect HAdV replication, as it too encodes many proteins with crucial nuclear functions (36).

Inhibition of Human Adenovirus Replication by the Importin α/β1 Nuclear Import Inhibitor Ivermectin

インポーチンα/β1核輸入阻害剤イベルメクチンによるヒトアデノウイルス複製の阻害

Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms; however, individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA-approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro. This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of importin-α (Imp-α) to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy.

ABSTRACT

Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin’s broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import.

▸ Sci Rep. 2018 Aug 9;8:11926. doi: 10.1038/s41598-018-30158-6

Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways

Nilambra Dogra 1,2, Ashok Kumar 1,3, Tapas Mukhopadhyay 1,

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Copyright and License information

PMCID: PMC6085345 PMID: 30093705

Abstract

Drugs that are already clinically approved or experimentally tested for conditions other than cancer, but are found to possess previously unrecognized cytotoxicity towards malignant cells, may serve as fitting anti-cancer candidates. Methyl N-(6-phenylsulfanyl- 1H benzimidazol-2-yl) carbamate [Fenbendazole, FZ], a benzimidazole compound, is a safe and inexpensive anthelmintic drug possessing an efficient anti-proliferative activity. In our earlier work, we reported a potent growth-inhibitory activity of FZ caused partially by impairment of proteasomal function. Here, we show that FZ demonstrates moderate affinity for mammalian tubulin and exerts cytotoxicity to human cancer cells at micromolar concentrations. Simultaneously, it caused mitochondrial translocation of p53 and effectively inhibited glucose uptake, expression of GLUT transporters as well as hexokinase (HK II) - a key glycolytic enzyme that most cancer cells thrive on. It blocked the growth of human xenografts in nu/nu mice model when mice were fed with the drug orally. The results, in conjunction with our earlier data, suggest that FZ is a new microtubule interfering agent that displays anti-neoplastic activity and may be evaluated as a potential therapeutic agent because of its effect on multiple cellular pathways leading to effective elimination of cancer cells.

Ivermectin and fenbendazole, primarily known as antiparasitic agents, have been studied for their interactions with the p53 tumor suppressor protein, revealing potential anticancer properties.

Ivermectin:

Mutant p53 Nuclear Translocation: Ivermectin can inhibit the nuclear import of mutant p53

proteins. In studies involving geranylgeranoic acid (GGA), which induces the nuclear translocation of mutant p53, ivermectin blocked this translocation, suggesting its role in modulating p53 localization.

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Reduction of Mutant p53 Levels: Ivermectin has been shown to reduce levels of mutated p53. Mutations in p53 can inactivate its tumor suppressor function or endow a gain-of- function phenotype. By reducing mutant p53 levels, ivermectin may influence cancer cell

behavior. MDPI

Fenbendazole:

Activation of p53 Pathway: Fenbendazole has been observed to increase the protein levels

of p53 and its downstream effector p21, indicating activation of the p53-p21 pathway. This activation leads to cell cycle arrest and apoptosis in cancer cells. MDPI

Downregulation of p53 Negative Regulators: Treatment with fenbendazole results in

decreased levels of Mdm2 and MdmX, which are negative regulators of p53. This downregulation contributes to the stabilization and activation of p53, enhancing its tumor suppressor functions. MDPI

Induction of Apoptosis: Fenbendazole promotes cell death by activating p53-mediated apoptosis pathways in certain cancer cell lines, highlighting its potential as an anticancer agent.

SYNAPSE

In summary, both ivermectin and fenbendazole interact with the p53 pathway, influencing its activity and stability. These interactions contribute to their potential anticancer effects, making them subjects of interest in oncology research.

For a more in-depth understanding, you may refer to the following studies:

Induction of nuclear translocation of mutant cytoplasmic p53 by GGA:

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Benzimidazoles Downregulate Mdm2 and MdmX and Activate p53 in Melanoma Cells:

MDPI

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Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells: