RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals

Abstract

Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interfering RNA (siRNA) loss-of-function screen of IV replication in A549 cells. Analysis of four different IV strains including a highly pathogenic avian H5N1 strain, an influenza B virus (IBV) and two human influenza A viruses (IAVs) revealed 133 genes required by all four IV strains. According to gene enrichment analyses, these strain-independent host genes were particularly enriched for nucleocytoplasmic trafficking. In addition, 360 strain-specific genes were identified with distinct patterns of usage for IAVs versus IBV and human versus avian IVs. The strain-independent host genes served to define 43 experimental and otherwise clinically approved drugs, targeting reportedly fourteen of the encoded host factors. Amongst the approved drugs, the urea-based kinase inhibitors (UBKIs) regorafenib and sorafenib exhibited a superior therapeutic window of high IV antiviral activity and low cytotoxicity. Both UBKIs appeared to block a cell signaling pathway involved in IV replication after internalization, yet prior to vRNP uncoating. Interestingly, both compounds were active also against unrelated viruses including cowpox virus (CPXV), hantavirus (HTV), herpes simplex virus 1 (HSV1) and vesicular stomatitis virus (VSV) and showed antiviral efficacy in human primary respiratory cells. An in vitro resistance development analysis for regorafenib failed to detect IV resistance development against this drug. Taken together, the otherwise clinically approved UBKIs regorafenib and sorafenib possess high and broad-spectrum antiviral activity along with substantial robustness against resistance development and thus constitute attractive host-directed drug candidates against a range of viral infections including influenza.

Identification of new drug treatments to combat COVID19: A signature-based approach using iLINCS

“…Kinase inhibitors are high-yield targets, with new small molecule kinase inhibitors being developed every year and over two dozen small molecule kinase inhibitors already approved for human use 97 . Their potential as antiviral treatments has also been explored in recent years 91 , 98 – 100 . Viruses depend on host cell protein kinases for every step of their life cycle, including viral entry into the cell, cell cycle processes and cellular stress response 101 .…”

Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury

“…All of these drugs were identified based on an understanding of the molecular mechanism of ALI. Although a few studies have been performed based on a group of genes, their results were not confirmed by well-designed experiments [10][11][12]. Thus, a genomic approach to identify drugs for potential repurposing is worth exploring, and in this work, we propose a highly efficient, genome-wide method to identify drugs to be repurposed for the treatment of ALI induced by H5N1 influenza virus infection.…”

Combined siRNA and Small-Molecule Phenotypic Screening Identifies Targets Regulating Rhinovirus Replication in Primary Human Bronchial Epithelial Cells

“…Interestingly, Lesch et al identified available compounds for a similar proportion of the hits from their influenza virus siRNA screen (43 compounds covering 14 of the total 133 hit genes). 38 We might have been able to identify more targets using this combination screening approach if more compounds covering more primary siRNA hits had been available. Therefore, the success of this combination screening approach highly depends on the availability of small-molecule compounds.…”

“…A similar approach has recently been reported in the search for host targets against influenza virus infection, whereby experimental or clinically approved drugs were selected based on the hits from an siRNA screen, enabling the identification of a host signaling pathway for targeting influenza virus. 38 Based on this hypothesis, we searched within the AstraZeneca compound collection for compounds that are annotated to be pharmacological regulators of the 1128 target genes. Only 122 targets had available compounds in the AstraZeneca compound collection.…”