RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals.
A549 Cells
Active Transport, Cell Nucleus
/ physiology
Antiviral Agents
Host-Pathogen Interactions
Humans
Influenza A Virus, H5N1 Subtype
/ genetics
Influenza A virus
/ genetics
Influenza B virus
/ genetics
Influenza, Human
Orthomyxoviridae
/ genetics
Phenylurea Compounds
/ pharmacology
Protein Kinase Inhibitors
/ metabolism
Pyridines
/ pharmacology
RNA Interference
/ immunology
RNA Viruses
RNA, Small Interfering
/ genetics
Sorafenib
/ pharmacology
Urea
/ metabolism
Virus Replication
/ physiology
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
21
12
2015
accepted:
29
01
2019
entrez:
19
3
2019
pubmed:
19
3
2019
medline:
12
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30883607
doi: 10.1371/journal.ppat.1007601
pii: PPATHOGENS-D-15-02950
pmc: PMC6422253
doi:
Substances chimiques
Antiviral Agents
0
Phenylurea Compounds
0
Protein Kinase Inhibitors
0
Pyridines
0
RNA, Small Interfering
0
regorafenib
24T2A1DOYB
Urea
8W8T17847W
Sorafenib
9ZOQ3TZI87
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1007601Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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