Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA.
The internal ribosome entry site (IRES), a highly conserved structured element of the hepatitis C virus (HCV) genomic RNA, is an attractive target for antiviral drugs. Here we show that benzimidazole inhibitors of the HCV replicon act by conformational induction of a widened interhelical angle in the IRES subdomain IIa, which facilitates the undocking of subdomain IIb from the ribosome and ultimately leads to inhibition of IRES-driven translation in HCV-infected cells.
Parsons
Jerod
J
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
Castaldi
M Paola
MP
Dutta
Sanjay
S
Dibrov
Sergey M
SM
Wyles
David L
DL
Hermann
Thomas
T
D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D003596:Cytosine / Q000737:chemistry; D016679:Genome, Viral / Q000187:drug effects; D005838:Genotype; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction
D000998:Antiviral Agents; D001562:Benzimidazoles; D012367:RNA, Viral; D003596:Cytosine; D008274:Magnesium