Benzimidazole analogs inhibit respiratory syncytial virus G protein function

Carrie W. Evans, Colm Atkins, Ashish Pathak, Brian E. Gilbert, James W. Noah

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Abstract 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.

Original languageEnglish (US)
Article number3656
Pages (from-to)31-38
Number of pages8
JournalAntiviral Research
Volume121
DOIs
StatePublished - Jul 3 2015

Fingerprint

Human respiratory syncytial virus
Respiratory Syncytial Viruses
GTP-Binding Proteins
Sigmodontinae
High-Throughput Screening Assays
Respiratory Syncytial Virus Infections
Bronchiolitis
Mortality
Viral Proteins
Virus Diseases
Virus Replication
Viral Load
Antiviral Agents
Heparin
benzimidazole
Pneumonia
Hospitalization
Vaccines
Pediatrics
Viruses

Keywords

  • Antiviral
  • G protein
  • Heparin
  • hRSV
  • SAR

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Evans, C. W., Atkins, C., Pathak, A., Gilbert, B. E., & Noah, J. W. (2015). Benzimidazole analogs inhibit respiratory syncytial virus G protein function. Antiviral Research, 121, 31-38. [3656]. https://doi.org/10.1016/j.antiviral.2015.06.016

Benzimidazole analogs inhibit respiratory syncytial virus G protein function. / Evans, Carrie W.; Atkins, Colm; Pathak, Ashish; Gilbert, Brian E.; Noah, James W.

In: Antiviral Research, Vol. 121, 3656, 03.07.2015, p. 31-38.

Research output: Contribution to journalArticle

Evans, CW, Atkins, C, Pathak, A, Gilbert, BE & Noah, JW 2015, 'Benzimidazole analogs inhibit respiratory syncytial virus G protein function', Antiviral Research, vol. 121, 3656, pp. 31-38. https://doi.org/10.1016/j.antiviral.2015.06.016
Evans, Carrie W. ; Atkins, Colm ; Pathak, Ashish ; Gilbert, Brian E. ; Noah, James W. / Benzimidazole analogs inhibit respiratory syncytial virus G protein function. In: Antiviral Research. 2015 ; Vol. 121. pp. 31-38.
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AB - Abstract 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.

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