Rational design of a deuterium-containing M2-S31N channel blocker UAWJ280 within vivoantiviral efficacy against both oseltamivir sensitive and -resistant influenza A viruses

Abstract

Seasonal influenza A virus (IAV) infections are among the most important global health problems. FDA-approved antiviral therapies against IAV include neuraminidase inhibitors, M2 inhibitors, and polymerase inhibitor baloxavir. Resistance against adamantanes (amantadine and rimantadine) is widespread as virtually all IAV strains currently circulating in the human population are resistant to adamantanes through the acquisition of the S31N mutation. The neuraminidase inhibitor-resistant strains also contain the M2-S31N mutant, suggesting M2-S31N is a high-profile antiviral drug target. Here we report the development of a novel deuterium-containing M2-S31N inhibitor UAWJ280. UAWJ280 had broad-spectrum antiviral activity against both oseltamivir sensitive and -resistant influenza A strains and had a synergistic antiviral effect in combination with oseltamivir in cell culture. In vivo pharmacokinetic (PK) studies demonstrated that UAWJ280 had favourable PK properties. The in vivo mouse model study showed that UAWJ280 was effective alone or in combination with oseltamivir in improving clinical signs and survival after lethal challenge with an oseltamivir sensitive IAV H1N1 strain. Furthermore, UAWJ280 was also able to ameliorate clinical signs and increase survival when mice were challenged with an oseltamivir-resistant IAV H1N1 strain. In conclusion, we show for the first time that the M2-S31N channel blocker UAWJ280 has in vivo antiviral efficacy in mice that are infected with either oseltamivir sensitive or -resistant IAVs, and it has a synergistic antiviral effect with oseltamivir.

Genome characterization of influenza A and B viruses in New South Wales, Australia, in 2019: A retrospective study using high‐throughput whole genome sequencing

“…Our genotypic screening found no evidence of this variant in all influenza virus strains tested, suggesting that Xofluza remains an effective treatment alternative to NAIs in Australia. Several novel antiviral drugs targeting different influenza viral proteins (including PB2, PB1, PA, M2, and NA) are under development 56–58 . With the increased use of diverse antiviral drugs in the future, it is expected that more drug‐resistant mutations may emerge across the entire genome.…”

FLUAV RAM-IGIP: A modified live influenza virus vaccine that enhances humoral and mucosal responses against influenza

“…At 5- and 20-dpi, a subset of mice (n=4/group/time point) were anesthetized, bled, and humanely euthanized to collect different fluids and tissues. At 21 dpi, a subset of mice (n=12/group) were challenged with 1×10 6 TCID50/mouse (∼1,000 mice lethal dose 50) of WT Ca/04 (14, 53). At 5 days post-challenge (5 dpc), a subset of mice (n=4/group, n=2/mock unvaccinated non-challenged control) were anesthetized, bled, and humanely euthanized to collect sera and different tissues.…”

“…Hemagglutination inhibition assays: Serum samples were collected at 20 dpi and 14 dpb to screen for the presence of neutralizing antibodies by hemagglutination inhibition (HAI) assays as previously described (53). Briefly, the sera were treated with receptor-destroying enzyme (Denka Seiken, VWR), incubated overnight at 37ºC, and then inactivated at 56ºC for 30 min.…”

Arbidol: The current demand, strategies, and antiviral mechanisms

“…M2 channel blockers, including amantadine and rimantadine, are common antiviral drugs that can inhibit the M2 ion channel activity for preventing the replication of the influenza virus 36 . Most influenza A viruses carry S31N mutation in their M2 genes 37 ; UAWJ280, a novel deuterium‐containing M2‐S31N inhibitor, demonstrated antiviral effect in mice infected with oseltamivir (OSV)‐sensitive or drug‐resistant influenza A viruses 38 . In 2021, the efficacy of two adamantane azaheterocyclic rimantadine derivatives on pneumonia caused by the rimantadine‐resistant influenza A virus in mice was reported 39 .…”