Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation

Brogi, Simone

doi:10.3390/v15102042

Cited by 4 publications

(3 citation statements)

References 17 publications

(17 reference statements)

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“…However, achieving normalized practical application may need additional studies in comparison to normal single-drug development. Continued research in this area is crucial for improving our ability to respond to emerging virus threats [62].…”

Section: Discussionmentioning

confidence: 99%

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Betancur-Galvis,

Jimenez-Jarava,

Rivas

et al. 2023

Pharmaceuticals

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Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction in the antiviral effective concentration of drugs already approved by the FDA, such as ivermectin (IVM), ribavirin (RIBA), and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV), and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecules with broad-spectrum antiviral activity, the ferruginol analog 18-(phthalimid-2-yl)ferruginol (phthFGL), which presented an IC99 of 25.6 μM for the three types of virus. In general, the combination of IVM, phthFGL, and oregano EO showed the greatest synergism potential against CHIKV, ZIKV, and HHV-2. For instance, this combination achieved reductions in the IC99 value of each component up to ~8-, ~27-, and ~12-fold for CHIKV, respectively. The ternary combination of RIBA, phthFGL, and oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, and oregano EO, which indicates that IVM could contribute more to the differentiation of cell targets (for example via the inhibition of the host heterodimeric importin IMP α/β1 complex) than ribavirin. Statistical analysis showed significant differences among the combination groups tested, especially in the HHV-2 and CHIKV models, with p = 0.0098. Additionally, phthFGL showed a good pharmacokinetic profile that should encourage future optimization studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Betancur-Galvis,

Jimenez-Jarava,

Rivas

et al. 2023

Pharmaceuticals

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show abstract

“…In the future, further studies of drug-drug interactions with commercially available medications will enable individuals to quickly take some medications at home for a few days to prevent severe illness before being attended to by the governmental healthcare system. Continued research in this area is crucial for improving our ability to respond to emerging virus threats [61].…”

Section: Discussionmentioning

confidence: 99%

Synergistic in vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils and 18-(Phthalimid-2-yl)ferruginol Against Arboviruses and Herpesvirus

Betancur-Galvis,

Jimenez-Jarava,

Rivas

et al. 2023

Preprint

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Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction of antiviral effective concentration of drugs already approved by the FDA, such as ivermectin (IVM), ribavirin (RIBA) and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV) and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecule with broad-spectrum antiviral activity, the ferruginol analogue 18-(phthalimid-2-yl)ferruginol (phthFGL). In general, the combination of IVM, phthFGL and Oregano EO showed the greatest synergism potential against CHIKV, ZIKV and HHV-2, obtaining a reduction in the EC99 value of up to ~8, and ~27, and ~12-fold for CHIKV, in example, respectively. The ternary combination RIBA, phthFGL, Oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, Oregano EO which indicates that IVM could contribute more to the differentiations of cell targets (for example by inhibition of host heterodimeric importin IMP α/β1 complex) than ribavirin. PhthFGL showed a good pharmacokinetic profile.

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“…First of all, they promise more effective control of the virus in the earlier stages of infection, which would be critically important in the case of VZV infection. 164 Additionally, these agents may help curb the already existing spread in patients and prevent some of the complications such as the frequent postherpetic neuralgia that most often affects the elderly and immunocompromised patients. 165 One of the most promising developments on the VZV therapy horizon is the discovery of the bicyclic nucleoside analogues such as FV-100.…”

Section: Novel Antiviral Agentsmentioning

confidence: 99%

Varicella‐zoster virus‐related neurological complications: From infection to immunomodulatory therapies

Hakami,

Khan,

Abdulaziz

et al. 2024

Reviews in Medical Virology

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The Varicella‐zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV‐associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune‐mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune‐mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV‐induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV‐related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV‐induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.

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Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation

Abstract: Representing more than 20% of all deaths occurring worldwide, infectious diseases remain one of the main factors in both human and animal morbidity and mortality [...]

Cited by 4 publications

References 17 publications

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Synergistic In Vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils, and 18-(Phthalimid-2-yl)ferruginol against Arboviruses and Herpesvirus

Synergistic in vitro Antiviral Effect of Combinations of Ivermectin, Essential Oils and 18-(Phthalimid-2-yl)ferruginol Against Arboviruses and Herpesvirus

Varicella‐zoster virus‐related neurological complications: From infection to immunomodulatory therapies

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