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A recombinant Cedar virus based high-throughput screening assay for henipavirus antiviral discovery.
A recombinant Cedar virus based high-throughput screening assay for henipavirus antiviral discovery.
- Source :
-
Antiviral Research . Sep2021, Vol. 193, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
Abstract
- 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. • A high-throughput screening assay using the Henipavirus , Cedar virus, encoding luciferase (rCedV-Luc) was established. • A large diverse small molecule library was screened for compounds that inhibited rCedV-Luc infection and replication. • 4 compounds that inhibited rCedV replication also inhibited authentic Nipah virus replication. • 2 compounds had IC 50 concentrations of less than 10 μM for Nipah virus and less than 20 μM for Hendra virus. • rCedV-Luc is an authentic henipavirus platform that will accelerate the development of anti-henipavirus countermeasures. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01663542
- Volume :
- 193
- Database :
- Academic Search Index
- Journal :
- Antiviral Research
- Publication Type :
- Academic Journal
- Accession number :
- 151734240
- Full Text :
- https://doi.org/10.1016/j.antiviral.2021.105084