High Throughput Screening Targeting the Dengue NS3-NS5 Interface Identifies Antivirals against Dengue, Zika and West Nile Viruses.
Cells
; 11(4)2022 02 18.
Article
em En
| MEDLINE
| ID: mdl-35203378
ABSTRACT
Dengue virus (DENV) threatens almost 70% of the world's population, with no effective therapeutic currently available and controversy surrounding the one approved vaccine. A key factor in dengue viral replication is the interaction between DENV nonstructural proteins (NS) 5 and 3 (NS3) in the infected cell. Here, we perform a proof-of-principle high-throughput screen to identify compounds targeting the NS5-NS3 binding interface. We use a range of approaches to show for the first time that two small molecules-repurposed drugs I-OMe tyrphostin AG538 (I-OMe-AG238) and suramin hexasodium (SHS)-inhibit NS5-NS3 binding at low µM concentration through direct binding to NS5 that impacts thermostability. Importantly, both have strong antiviral activity at low µM concentrations against not only DENV-2, but also Zika virus (ZIKV) and West Nile virus (WNV). This work highlights the NS5-NS3 binding interface as a viable target for the development of anti-flaviviral therapeutics.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vírus do Nilo Ocidental
/
Dengue
/
Zika virus
/
Infecção por Zika virus
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
Cells
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Austrália