Benzimidazole analogs inhibit respiratory syncytial virus G protein function

Autor: Brian E. Gilbert, Colm Atkins, James W. Noah, Carrie W. Evans, Ashish K. Pathak
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Antiviral Research
ISSN: 1872-9096
0166-3542
Popis: Highlights • We used HTS to identify a lead compound that inhibited hRSV replication in vitro. • Analog compounds were characterized for structure activity relationships. • An hRSV lead compound-resistant mutant had a mutation in the hRSV G protein. • The lead compound activity in different cell types correlates with G protein function. • The lead compound did not reduce RSV pathogenicity in a cotton rat model.
Human respiratory syncytial virus (hRSV) is a highly contagious Paramyxovirus that infects most children by age two, generating an estimated 75,000–125,000 hospitalizations in the U.S. annually. hRSV is the most common cause of bronchiolitis and pneumonia among infants and children under 1 year of age, with significant mortality among high-risk groups. A regulatory agency-approved vaccine is not available, and existing prophylaxis and therapies are limited to use in high-risk pediatric patients; thus additional therapies are sorely needed. Here, we identify a series of benzimidazole analogs that inhibit hRSV infection in vitro with high potency, using a previously-reported high-throughput screening assay. The lead compound, SRI 29365 (1-[6-(2-furyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]methyl-1H-benzimidazole), has an EC50 of 66 μM and a selectivity >50. We identified additional compounds with varying potencies by testing commercially-available chemical analogs. Time-of-addition experiments indicated that SRI 29365 effectively inhibits viral replication only if present during the early stages of viral infection. We isolated a virus with resistance to SRI 29365 and identified mutations in the transmembrane domain of the viral G protein genomic sequence that suggested that the compound inhibits G-protein mediated attachment of hRSV to cells. Additional experiments with multiple cell types indicated that SRI 29365 antiviral activity correlates with the binding of cell surface heparin by full-length G protein. Lastly, SRI 29365 did not reduce hRSV titers or morbidity/mortality in efficacy studies using a cotton rat model. Although SRI 29365 and analogs inhibit hRSV replication in vitro, this work suggests that the G-protein may not be a valid drug target in vivo.
Databáze: OpenAIRE
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