A recombinant Cedar virus based high-throughput screening assay for henipavirus antiviral discovery.
Antiviral Agents
/ pharmacology
Cell Line
Genes, Reporter
Henipavirus
/ drug effects
Henipavirus Infections
/ drug therapy
High-Throughput Screening Assays
Humans
Luciferases
/ genetics
Recombination, Genetic
Viral Envelope Proteins
/ genetics
Virus Internalization
/ drug effects
Virus Replication
/ drug effects
Antiviral
Cedar virus
Henipavirus
High-throughput screening assay
Inhibitor
Luciferase assay
Reverse genetics
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
24
08
2020
revised:
21
04
2021
accepted:
28
04
2021
pubmed:
3
6
2021
medline:
15
12
2021
entrez:
2
6
2021
Statut:
ppublish
Résumé
Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic, bat-borne paramyxoviruses in the genus Henipavirus that cause severe and often fatal acute respiratory and/or neurologic diseases in humans and livestock. There are currently no approved antiviral therapeutics or vaccines for use in humans to treat or prevent NiV or HeV infection. To facilitate development of henipavirus antivirals, a high-throughput screening (HTS) platform was developed based on a well-characterized recombinant version of the nonpathogenic Henipavirus, Cedar virus (rCedV). Using reverse genetics, a rCedV encoding firefly luciferase (rCedV-Luc) was rescued and its utility evaluated for high-throughput antiviral compound screening. The luciferase reporter gene signal kinetics of rCedV-Luc in different human cell lines was characterized and validated as an authentic real-time measure of viral growth. The rCedV-Luc platform was optimized as an HTS assay that demonstrated high sensitivity with robust Z' scores, excellent signal-to-background ratios and coefficients of variation. Eight candidate compounds that inhibited rCedV replication were identified for additional validation and demonstrated that 4 compounds inhibited authentic NiV-Bangladesh replication. Further evaluation of 2 of the 4 validated compounds in a 9-point dose response titration demonstrated potent antiviral activity against NiV-Bangladesh and HeV, with minimal cytotoxicity. This rCedV reporter can serve as a surrogate yet authentic BSL-2 henipavirus platform that will dramatically accelerate drug candidate identification in the development of anti-henipavirus therapies.
Identifiants
pubmed: 34077807
pii: S0166-3542(21)00074-7
doi: 10.1016/j.antiviral.2021.105084
pmc: PMC8631057
mid: NIHMS1712073
pii:
doi:
Substances chimiques
Antiviral Agents
0
Viral Envelope Proteins
0
Luciferases
EC 1.13.12.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
105084Subventions
Organisme : NIAID NIH HHS
ID : R21 AI137813
Pays : United States
Organisme : NIAID NIH HHS
ID : R41 AI157095
Pays : United States
Organisme : NIAID NIH HHS
ID : UC7 AI094660
Pays : United States
Informations de copyright
Published by Elsevier B.V.
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