Antiviral Mechanisms of N-Phenyl Benzamides on Coxsackie Virus A9
- Laajala, Mira, Kalander, Kerttu, Consalvi, Sara, Sheik Amamuddy, Olivier, Tastan Bishop, Özlem, Biava, Mariangela, Poce, Giovanna, Marjomäki, Varpu
- Authors: Laajala, Mira , Kalander, Kerttu , Consalvi, Sara , Sheik Amamuddy, Olivier , Tastan Bishop, Özlem , Biava, Mariangela , Poce, Giovanna , Marjomäki, Varpu
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/474448 , vital:77708 , https://doi.org/10.3390/pharmaceutics15031028
- Description: Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC50 value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion
- Full Text:
- Date Issued: 2023
- Authors: Laajala, Mira , Kalander, Kerttu , Consalvi, Sara , Sheik Amamuddy, Olivier , Tastan Bishop, Özlem , Biava, Mariangela , Poce, Giovanna , Marjomäki, Varpu
- Date: 2023
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/474448 , vital:77708 , https://doi.org/10.3390/pharmaceutics15031028
- Description: Enteroviruses are one of the most abundant groups of viruses infecting humans, and yet there are no approved antivirals against them. To find effective antiviral compounds against enterovirus B group viruses, an in-house chemical library was screened. The most effective compounds against Coxsackieviruses B3 (CVB3) and A9 (CVA9) were CL212 and CL213, two N-phenyl benzamides. Both compounds were more effective against CVA9 and CL213 gave a better EC50 value of 1 µM with high a specificity index of 140. Both drugs were most effective when incubated directly with viruses suggesting that they mainly bound to the virions. A real-time uncoating assay showed that the compounds stabilized the virions and radioactive sucrose gradient as well as TEM confirmed that the viruses stayed intact. A docking assay, taking into account larger areas around the 2-and 3-fold axes of CVA9 and CVB3, suggested that the hydrophobic pocket gives the strongest binding to CVA9 but revealed another binding site around the 3-fold axis which could contribute to the binding of the compounds. Together, our data support a direct antiviral mechanism against the virus capsid and suggest that the compounds bind to the hydrophobic pocket and 3-fold axis area resulting in the stabilization of the virion
- Full Text:
- Date Issued: 2023
Polyphenols Epigallocatechin Gallate and Resveratrol, and Polyphenol-Functionalized Nanoparticles Prevent Enterovirus Infection through Clustering and Stabilization of the Viruses
- Reshamwala, Dhanik, Sheik Amamuddy, Olivier, Laquintana, Valentino, Denora, Nunzio, Zacheo, Antonella, Lampinen, Vili, Hytonen, Vesa P, Tastan Bishop, Özlem, Krol, Silke, Marjomäki, Varpu
- Authors: Reshamwala, Dhanik , Sheik Amamuddy, Olivier , Laquintana, Valentino , Denora, Nunzio , Zacheo, Antonella , Lampinen, Vili , Hytonen, Vesa P , Tastan Bishop, Özlem , Krol, Silke , Marjomäki, Varpu
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476607 , vital:77941 , xlink:href="https://doi.org/10.3390/pharmaceutics13081182"
- Description: To efficiently lower virus infectivity and combat virus epidemics or pandemics, it is important to discover broadly acting antivirals. Here, we investigated two naturally occurring polyphenols, Epigallocatechin gallate (EGCG) and Resveratrol (RES), and polyphenol-functionalized nanoparticles for their antiviral efficacy. Concentrations in the low micromolar range permanently inhibited the infectivity of high doses of enteroviruses (107 PFU/mL). Sucrose gradient separation of radiolabeled viruses, dynamic light scattering, transmission electron microscopic imaging and an in-house developed real-time fluorescence assay revealed that polyphenols prevented infection mainly through clustering of the virions into very stable assemblies. Clustering and stabilization were not compromised even in dilute virus solutions or after diluting the polyphenols-clustered virions by 50-fold. In addition, the polyphenols lowered virus binding on cells. In silico docking experiments of these molecules against 2- and 3-fold symmetry axes of the capsid, using an algorithm developed for this study, discovered five binding sites for polyphenols, out of which three were novel binding sites. Our results altogether suggest that polyphenols exert their antiviral effect through binding to multiple sites on the virion surface, leading to aggregation of the virions and preventing RNA release and reducing cell surface binding.
- Full Text:
- Date Issued: 2021
- Authors: Reshamwala, Dhanik , Sheik Amamuddy, Olivier , Laquintana, Valentino , Denora, Nunzio , Zacheo, Antonella , Lampinen, Vili , Hytonen, Vesa P , Tastan Bishop, Özlem , Krol, Silke , Marjomäki, Varpu
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/476607 , vital:77941 , xlink:href="https://doi.org/10.3390/pharmaceutics13081182"
- Description: To efficiently lower virus infectivity and combat virus epidemics or pandemics, it is important to discover broadly acting antivirals. Here, we investigated two naturally occurring polyphenols, Epigallocatechin gallate (EGCG) and Resveratrol (RES), and polyphenol-functionalized nanoparticles for their antiviral efficacy. Concentrations in the low micromolar range permanently inhibited the infectivity of high doses of enteroviruses (107 PFU/mL). Sucrose gradient separation of radiolabeled viruses, dynamic light scattering, transmission electron microscopic imaging and an in-house developed real-time fluorescence assay revealed that polyphenols prevented infection mainly through clustering of the virions into very stable assemblies. Clustering and stabilization were not compromised even in dilute virus solutions or after diluting the polyphenols-clustered virions by 50-fold. In addition, the polyphenols lowered virus binding on cells. In silico docking experiments of these molecules against 2- and 3-fold symmetry axes of the capsid, using an algorithm developed for this study, discovered five binding sites for polyphenols, out of which three were novel binding sites. Our results altogether suggest that polyphenols exert their antiviral effect through binding to multiple sites on the virion surface, leading to aggregation of the virions and preventing RNA release and reducing cell surface binding.
- Full Text:
- Date Issued: 2021
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