In:
Journal of Virology, American Society for Microbiology, Vol. 80, No. 1 ( 2006-01), p. 149-160
Abstract:
We
report on the highly potent and selective antipestivirus activity of 5-[(4-bromophenyl)methyl]-2-phenyl-5 H -imidazo[4,5-c]pyridine (BPIP). The 50% effective concentration (EC 50 ) for
inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect formation was 0.04 ± 0.01 μM. Comparable
reduction of viral RNA synthesis (EC 50 = 0.12±
0.02 μM) and production of infectious virus (EC 50 = 0.074 ± 0.003 μM) were
observed. The selectivity index (ratio of 50% cytostatic concentration/EC 50 ) of BPIP was ∼2,000. BPIP was
inactive against the hepatitis C virus subgenomic replicon and yellow fever virus but demonstrated weak activity against GB
virus. Drug-resistant mutants were at least 300-fold less susceptible to BPIP than wild-type virus; showed cross-resistance to N -propyl- N -[2-(2 H -1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl] -1-propanamine
(VP32947), and carried the F224S mutation in the viral RNA-dependent RNA polymerase (RdRp). When the F224S mutation was introduced into an
infectious clone, the drug-resistant phenotype was obtained. BPIP did not inhibit the in vitro activity of recombinant BVDV RdRp, but did
inhibit the activity of replication complexes (RCs). Computational docking revealed that F224 is located at the top of the finger domain
of the polymerase. Docking of BPIP in the crystal structure of the BVDV RdRp revealed aromatic ring stacking, some hydrophobic contacts, and a
hydrogen bond. Since two structurally unrelated compounds, i.e., BPIP and VP32947, target the same region of the BVDV RdRp, this position may
be expected to be critical in the functioning of the polymerase or assembly of the RC. The potential of BPIP for the treatment of
pestivirus and hepacivirus infections is discussed.
Type of Medium:
Online Resource
ISSN:
0022-538X
,
1098-5514
DOI:
10.1128/JVI.80.1.149-160.2006
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2006
detail.hit.zdb_id:
1495529-5
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