Work

Host-targeted repurposed diltiazem enhances the antiviral activity of direct acting antivirals against Influenza A virus and SARS-CoV-2

Year: 2025

Type: article

Abstract: 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. • Proof-of-concept study on the combination of direct acting and host-targeted antivirals against two major respiratory viruses. • Repurposed diltiazem is a IFN-λ modulator and shows broad-spectrum antiviral activity against Influenza A virus and SARS-CoV-2. • The Diltiazem-Baloxavir combination is superior to both monotherapies against Influenza A wt and PA I38T resistant viruses. • The Diltiazem-Molnupiravir combination is superior to both monotherapies against SARS-CoV-2, including VOCs.

Source: Antiviral Research

DOI: 10.1016/j.antiviral.2025.106138