Ifenprodil and Flavopiridol Identified by Genomewide RNA Interference Screening as Effective Drugs To Ameliorate Murine Acute Lung Injury after Influenza A H5N1 Virus Infection

Abstract

Drug repurposing is a quick and economical strategy for developing new therapies with approved drugs. H5N1 is a highly pathogenic avian influenza virus subtype that can cause severe acute lung injury (ALI) and a high mortality rate due to limited treatments. The use of RNA interference (RNAi) is a reliable approach to identify essential genes in diseases. In most genomewide RNAi screenings, virus replication is the readout of interference. Since H5N1 virus infection could induce significant cell death and the percentage of cell death is associated with virus lethality, we designed a genomewide RNAi screening method to identify repurposable drugs against H5N1 virus with cell death as the readout. We discovered that the neurological drug ifenprodil and the anticancer drug flavopiridol could effectively ameliorate murine ALI after influenza A H5N1 virus infection, suggesting that they might be novel remedies for H5N1 virus-induced ALI in addition to the traditional indications.

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

“…These screens identified multiple genes for which knockdown altered cell viability and drugs targeting some of these genes were assayed for their potential antiviral activity. The neurological drug ifenprodil increased cell viability in vitro and markedly decreased leukocyte infiltration and lung injury, and improved survival of mice infected with H5N1 ( Zhang et al, 2019 ), the most lethal influenza virus strain. The effect of ifenprodil was discussed in the context of its antagonism at the N-methyl-D-aspartate (NMDA) receptor as overstimulation of the NMDA receptor can trigger lung injury.…”

SARS-CoV-2: The Monster Causes COVID-19

“…Li et al (Runfeng et al, 2020) pointed out that the traditional Chinese medicine Lianhuaqingwen could significantly inhibit the replication of SARS-CoV-2 in cells, and after the treatment of Lianhuaqingwen, the expression of cytokines induced by virus particles was significantly reduced (Table S1). Based on Zhang et al's research (Zhang et al, 2019), Ifenprodil is considered as a potential first-line drug for the treatment of COVID-19 (Table S1). Duan et al (2020) showed that plasma therapy may provide a useful therapeutic effect and a low risk in the treatment of severe COVID -19 patients (Table S1).…”

Repurposed Drugs, Molecular Vaccines, Immune‐Modulators, and Nanotherapeutics to Treat and Prevent COVID‐19 Associated with SARS‐CoV‐2, a Deadly Nanovector

“…NP-120 is N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist, which targets the NMDA-type subunit 2B (Glu2NB). [97] Ifenprodil is a vasodilator, originally developed by Sanofi as an oral medication to treat blood circulation disorders in French and Japanese markets. It is no longer sold in France but is still marketed in Japan.…”

“…An independent animal study showing a considerable reduction in ALI and enhanced survivability in Avian H5N1 infected mice encourages researchers to expand clinical programs to ALI and ARDS associated with COVID-19 infection. [97] An adaptive Phase IIb/III study assessing the safety and efficacy of ifenprodil (20/40 mg three times a day) together with standard of care in comparison to standard of care alone in the treatment of hospitalized COVID-19 patients is underway (NCT04382924). Ifenprodil is already being tested in clinical trials in patients suffering from IPF and its associated cough (NCT04318704).…”