Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity

Abstract

The high genetic variability of influenza A viruses poses a continual challenge to seasonal and pandemic vaccine development, leaving antiviral drugs as the first line of defense against antigenically different strains or new subtypes. As resistance against drugs targeting viral proteins emerges rapidly, we assessed the antiviral activity of already approved drugs that target cellular proteins involved in the viral life cycle and were orally bioavailable. Out of 15 candidate compounds, four were able to inhibit infection by 10- to 100-fold without causing toxicity, in vitro . Two of the drugs, dextromethorphan and ketotifen, displayed a 50% effective dose between 5 and 50 μM, not only for the classic H1N1 PR8 strain, but also for a pandemic H1N1 and a seasonal H3N2 strain. Efficacy assessment in mice revealed that dextromethorphan consistently resulted in a significant reduction of viral lung titers and also enhanced the efficacy of oseltamivir. Dextromethorphan treatment of ferrets infected with a pandemic H1N1 strain led to a reduction in clinical disease severity, but no effect on viral titer was observed. In addition to identifying dextromethorphan as a potential influenza treatment option, our study illustrates the feasibility of a bioinformatics-driven rational approach for repurposing approved drugs against infectious diseases.

In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2

“…Mast cells can intensify immunological injury through the production of mediators, including tryptase, TNF-α, IL-6, IL-1, and chemokine (C-C motif) ligand 3 (CCL3). Animal studies have shown that ketotifen can reduce excessive inflammation (cytokine storm), and ketotifen has been shown to reduce end organ damage and mortality in mice infected with H5N1 type Influenza A [ 42 ]. Ketotifen has been shown in mice infected with H5N1 influenza viral to dramatically reduce lung damage and mortality, even when the antiviral, oseltamivir, was dosed sub-optimally (ketotifen and oseltamivir 100% survival vs. oseltamivir alone 65%) [ 43 ].…”

Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase

“…Broad-spectrum anti-paramyxovirus drug candidates that inhibit at least one family member with predictable disease burden in adults may offer a viable path to establish clinical proof-of-concept; provide benefit to a larger patient pool suffering from diverse paramyxovirus infections to better offset developmental costs; and widen windows of opportunity against at least some indications, since disease progression profiles vary between paramyxoviruses. However, traditional broad-spectrum antivirals are host-directed 14 – 19 or ribonucleoside analogs 20 – 23 that are unlikely to meet the tight safety profile necessary for pediatric use and therefore make poor anti-paramyxovirus candidates overall. Allosteric direct-acting antivirals are better suited to deliver the required safety margin, but are typically restricted to a single paramyxovirus target.…”

Insights into the biased activity of dextromethorphan and haloperidol towards SARS-CoV-2 NSP6: in silico binding mechanistic analysis

“…More importantly, Theresa Enkirch et al [ 27 ] had evaluated the anti-influenza activity of dextromethorphan in vitro, and in mice as well as in animal models. The authors demonstrated that dextromethorphan was able to inhibit viral replication both in vitro and in vivo.…”