Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

Theerawatanasirikul, Sirin; Lueangaramkul, Varanya; Semkum, Ploypailin; Lekcharoensuk, Porntippa

doi:10.1007/s11259-023-10211-0

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…The SOR presence likewise resulted in a reduction in the amplitude of I K(IR) , as observed in neonatal rat ventricular myocytes. This inhibition of ionic currents during SOR exposure may constitute an unintended yet crucial mechanism, contributing to alterations in QTc intervals or possibly influencing antiviral effects [9,19,[82][83][84]. These findings could offer insights into the occurrence of patients exhibiting QTc prolongation and, in some cases, experiencing subsequent fatal arrhythmias following treatment with SOR [10,85].…”

Section: Sm-102mentioning

confidence: 99%

“…Strategies for dose escalation have been contemplated for their clinical use, given that many malignancies are believed to be instigated by aberrant tyrosine kinase activity [81]. Tyrosine kinase inhibitors, such as sunitinib and SOtR, have recently been noticed to exert antiviral action [82][83][84]. A previous report has demonstrated the ability of SOR to suppress the amplitude of both the slowly activating delayed-rectifier K + current (I K(S) ) and I K(erg) identified in H9c2 cardiomyocytes [19,22].…”

Section: Sm-102mentioning

confidence: 99%

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Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

Lin,

Shih,

Liutkevičienė

et al. 2024

Biophysica

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As the need for effective antiviral treatment intensifies, such as with the coronavirus disease 19 (COVID-19) infection, it is crucial to understand that while the mechanisms of action of these drugs or compounds seem apparent, they might also interact with unexplored targets, such as cell membrane ion channels in diverse cell types. In this review paper, we demonstrate that many different drugs or compounds, in addition to their known interference with viral infections, may also directly influence various types of ionic currents on the surface membrane of the host cell. These agents include artemisinin, cannabidiol, memantine, mitoxantrone, molnupiravir, remdesivir, SM-102, and sorafenib. If achievable at low concentrations, these regulatory effects on ion channels are highly likely to synergize with the identified initial mechanisms of viral replication interference. Additionally, the immediate regulatory impact of these agents on the ion-channel function may potentially result in unintended adverse effects, including changes in cardiac electrical activity and the prolongation of the QTc interval. Therefore, it is essential for patients receiving these related agents to exercise additional caution to prevent unnecessary complications.

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Section: Sm-102mentioning

confidence: 99%

Section: Sm-102mentioning

confidence: 99%

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

Lin,

Shih,

Liutkevičienė

et al. 2024

Biophysica

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“…Sorafenib, a c-RAF and multi-kinase inhibitor, is approved for treating liver cancer [ 137 ]. Drug repurposing of sorafenib has been shown to inhibit viral replication in a wide range of viruses, and recent studies have found that sorafenib targets the FMDV 3D pol active site, inhibiting polymerase activity and modulating the c-RAF and AKT/PI3K pathways to inhibit FMDV replication [ 138 ].…”

Section: Drugs Acting On 3d Polmentioning

confidence: 99%

The multiple roles of viral 3D ^pol protein in picornavirus infections

Nie,

Zhai,

Zhang

et al. 2024

Virulence

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The Picornaviridae are a large group of positive-sense, single-stranded RNA viruses, and most research has focused on the Enterovirus genus, given they present a severe health risk to humans. Other picornaviruses, such as foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), affect agricultural production with high animal mortality to cause huge economic losses. The 3D pol protein of picornaviruses is widely known to be used for genome replication; however, a growing number of studies have demonstrated its non-polymerase roles, including modulation of host cell biological processes, viral replication complex assembly and localization, autophagy, and innate immune responses. Currently, there is no effective vaccine to control picornavirus diseases widely, and clinical therapeutic strategies have limited efficiency in combating infections. Many efforts have been made to develop different types of drugs to prohibit virus survival; the most important target for drug development is the virus polymerase, a necessary element for virus replication. For picornaviruses, there are also active efforts in targeted 3D pol drug development. This paper reviews the interaction of 3D pol proteins with the host and the progress of drug development targeting 3D pol .

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Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

Pantanam,

Mana,

Semkum

et al. 2024

International Journal of Veterinary Science and Medicine

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Foot-and-Mouth Disease (FMD) is a contagious, blistering disease caused by the Foot-and-Mouth Disease virus (FMDV), which affects livestock globally. Currently, no commercial antiviral agent is available for effective disease control. This study investigated the antiviral potential of natural-derived alkaloids against FMDV in BHK-21 cells. Twelve alkaloids were assessed for their antiviral activities at various stages of FMDV infection, including pre-viral entry, post-viral entry, and prophylactic assays, as well as attachment and penetration assays by evaluating cytopathic effect reduction and directed-virucidal effects. The results showed that ipecac alkaloids, cephaeline (CPL) and emetine (EMT), exhibited dual effects with robust antiviral efficacy by reducing cytopathic effect and inhibiting FMDV replication in a dose-dependent manner. Evaluation through immunoperoxidase monolayer assay and RT-PCR indicated effectiveness at post-viral entry stage, with sub-micromolar EC 50 values for CPL and EMT at 0.05 and 0.24 µM, respectively, and high selective indices. Prophylactic effects prevented infection with EC 50 values of 0.23 and 0.64 µM, respectively. Directed-virucidal effects demonstrated significant reduction of extracellular FMDV, with CPL exhibiting a dose-dependent effect. Furthermore, the replicase (3Dpol) inhibition activity was identified using the FMDV minigenome assay, which revealed strong inhibition with IC 50 values of 0.15 µM for CPL and 4.20 µM for EMT, consistent with the decreased negative-stranded RNA production. Molecular docking confirmed the interaction of CPL and EMT with residues in the active site of FMDV 3Dpol. In conclusion, CPL and EMT exhibited promising efficacy through their dual effects and provide an alternative approach for controlling FMD in livestock.

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Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

Cited by 4 publications

References 47 publications

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

The multiple roles of viral 3D ^pol protein in picornavirus infections

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

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Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

Cited by 4 publications

References 47 publications

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

Assessing the Impact of Agents with Antiviral Activities on Transmembrane Ionic Currents: Exploring Possible Unintended Actions

The multiple roles of viral 3D pol protein in picornavirus infections

Dual effects of ipecac alkaloids with potent antiviral activity against foot-and-mouth disease virus as replicase inhibitors and direct virucides

Contact Info

Product

Resources

About

The multiple roles of viral 3D ^pol protein in picornavirus infections