tetano
Editor, Senior Moderator
Antiviral Res
. 2025 Mar 4:106138.
doi: 10.1016/j.antiviral.2025.106138. Online ahead of print. Host-targeted repurposed diltiazem enhances the antiviral activity of direct acting antivirals against Influenza A virus and SARS-CoV-2
Blandine Padey[SUP] 1 [/SUP], Clément Droillard[SUP] 2 [/SUP], Victoria Dulière[SUP] 2 [/SUP], Julien Fouret[SUP] 3 [/SUP], Claire Nicolas de Lamballerie[SUP] 1 [/SUP], Cédrine Milesi[SUP] 2 [/SUP], Emilie Laurent[SUP] 2 [/SUP], Pauline Brun[SUP] 2 [/SUP], Aurélien Traversier[SUP] 2 [/SUP], Thomas Julien[SUP] 2 [/SUP], Olivier Terrier[SUP] 4 [/SUP], Manuel Rosa-Calatrava[SUP] 5 [/SUP], Andrés Pizzorno[SUP] 6 [/SUP]
Affiliations
Viral respiratory infections remain a major and recurrent public health threat. Among them, influenza viruses are responsible for ⁓500,000 deaths worldwide and a high economic burden. The recurrent threat of emerging zoonotic or pandemic viruses worsens this scenario, being SARS-CoV-2 and the millions of COVID-19 deaths the most recent example. The rapid evolution of circulating influenza and SARS-CoV-2 viruses allows the emergence and dissemination of variant strains carrying mutations resulting in suboptimal vaccine protection and/or reduced efficacy of current limited therapeutic arsenal. In this context, host-targeted approaches constitute a promising antiviral strategy aiming to achieve broad-spectrum activity and mitigate the emergence of viral resistance against classic direct acting antivirals. Here, we demonstrated that diltiazem, a calcium channel blocker currently used to treat angor, induces an ISG expression profile characteristic of an antiviral cellular state mainly driven by IFN-λ. We then evaluated the potential of the diltiazem-baloxavir combination against Influenza A wild-type and the PA I38T resistant strain in cell culture and human airway epithelia (HAE). We analogously evaluated the diltiazem-molnupiravir combination against SARS-CoV-2, including variants of concern. Our results demonstrate the broad-spectrum antiviral activity of diltiazem against Influenza A viruses, including resistant strains, as well as the capacity to potentiate the antiviral effect of baloxavir. The diltiazem-molnupiravir combination further reduced viral production and protected the integrity of HAE infected with SARS-CoV-2. This study highlights the major interest of combining direct acting and host-targeted agents as a promising strategy against circulating and emerging viruses.
Keywords: SARS-CoV-2; antiviral resistance; diltiazem; direct acting antivirals (DAA); drug combination; host-targeted antivirals (HTA); influenza; interferon; respiratory viruses.
. 2025 Mar 4:106138.
doi: 10.1016/j.antiviral.2025.106138. Online ahead of print. Host-targeted repurposed diltiazem enhances the antiviral activity of direct acting antivirals against Influenza A virus and SARS-CoV-2
Blandine Padey[SUP] 1 [/SUP], Clément Droillard[SUP] 2 [/SUP], Victoria Dulière[SUP] 2 [/SUP], Julien Fouret[SUP] 3 [/SUP], Claire Nicolas de Lamballerie[SUP] 1 [/SUP], Cédrine Milesi[SUP] 2 [/SUP], Emilie Laurent[SUP] 2 [/SUP], Pauline Brun[SUP] 2 [/SUP], Aurélien Traversier[SUP] 2 [/SUP], Thomas Julien[SUP] 2 [/SUP], Olivier Terrier[SUP] 4 [/SUP], Manuel Rosa-Calatrava[SUP] 5 [/SUP], Andrés Pizzorno[SUP] 6 [/SUP]
Affiliations
- PMID: 40049293
- DOI: 10.1016/j.antiviral.2025.106138
Viral respiratory infections remain a major and recurrent public health threat. Among them, influenza viruses are responsible for ⁓500,000 deaths worldwide and a high economic burden. The recurrent threat of emerging zoonotic or pandemic viruses worsens this scenario, being SARS-CoV-2 and the millions of COVID-19 deaths the most recent example. The rapid evolution of circulating influenza and SARS-CoV-2 viruses allows the emergence and dissemination of variant strains carrying mutations resulting in suboptimal vaccine protection and/or reduced efficacy of current limited therapeutic arsenal. In this context, host-targeted approaches constitute a promising antiviral strategy aiming to achieve broad-spectrum activity and mitigate the emergence of viral resistance against classic direct acting antivirals. Here, we demonstrated that diltiazem, a calcium channel blocker currently used to treat angor, induces an ISG expression profile characteristic of an antiviral cellular state mainly driven by IFN-λ. We then evaluated the potential of the diltiazem-baloxavir combination against Influenza A wild-type and the PA I38T resistant strain in cell culture and human airway epithelia (HAE). We analogously evaluated the diltiazem-molnupiravir combination against SARS-CoV-2, including variants of concern. Our results demonstrate the broad-spectrum antiviral activity of diltiazem against Influenza A viruses, including resistant strains, as well as the capacity to potentiate the antiviral effect of baloxavir. The diltiazem-molnupiravir combination further reduced viral production and protected the integrity of HAE infected with SARS-CoV-2. This study highlights the major interest of combining direct acting and host-targeted agents as a promising strategy against circulating and emerging viruses.
Keywords: SARS-CoV-2; antiviral resistance; diltiazem; direct acting antivirals (DAA); drug combination; host-targeted antivirals (HTA); influenza; interferon; respiratory viruses.