Host-Directed Repurposed Diltiazem Enhances the Antiviral Activity of Classic Antivirals Against Influenza and Sars-Cov-2

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 virus-directed 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 virus-directed and host-directed agents as a promising strategy against circulating and emerging viruses.

Note:
Funding Information: This work was funded by the European Innovation Council and SMEs Executive Agency (EISMEA) EIC Accelerator Instrument (grant agreement 954353 – Signia), and INSERM REACTing (REsearch & ACtion emergING infectious diseases), CNRS, and Mérieux research grants. BP was supported by an ANRT CIFRE PhD scholarship.

Declaration of Interests: BP, CNdL, AT, TJ, OT and MRC and AP are co-inventors on patents or patent applications filed by INSERM, CNRS, Université Claude Bernard Lyon 1 and Signia Therapeutics for the repurposing of diltiazem for the treatment of viral respiratory infections, including influenza and SARS-CoV-2.

No other conflicts declared.

Keywords: diltiazem, host-directed antivirals, drug combination, Respiratory Viruses, Influenza, SARS-COV-2