Conformational inhibition of the HCV IRES RNA
نویسندگان
چکیده
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.
منابع مشابه
Conformational inhibition of the hepatitis C virus internal ribosome entry site RNA
HCV infection affects ~170 million people worldwide and is a major cause of chronic hepatitis as well as hepatocellular carcinoma1. Current therapies suffer from low efficiency and serious side effects. Therefore, there is an urgent need for new antiviral agents for the treatment of HCV infection. Among the potential targets for HCV inhibitors is the highly conserved 5′ untranslated region (UTR...
متن کاملLocking out viral replication.
by a single A→U point mutation3. Both the benzimidazole derivative and the mutation reduce the production of viral proteins by approximately 80%, likely by preventing formation of the complete 80S eukaryotic ribosome. Hence this small molecule does not function by competitively inhibiting the interaction between the IRES and its target. Instead, it affects IRESdriven viral protein synthesis by ...
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Human La protein is known to interact with hepatitis C virus (HCV) internal ribosome entry site (IRES) and stimulate translation. Previously, we demonstrated that mutations within HCV SL IV lead to reduced binding to La-RNA recognition motif 2 (RRM2) and drastically affect HCV IRES-mediated translation. Also, the binding of La protein to SL IV of HCV IRES was shown to impart conformational alte...
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HCV NS3 protein plays a central role in viral polyprotein processing and RNA replication. We demonstrate that the NS3 protease (NS3(pro)) domain alone can specifically bind to HCV-IRES RNA, predominantly in the SLIV region. The cleavage activity of the NS3 protease domain is reduced upon HCV-RNA binding. More importantly, NS3(pro) binding to the SLIV hinders the interaction of La protein, a cel...
متن کاملHCV IRES interacts with the 18S rRNA to activate the 40S ribosome for subsequent steps of translation initiation
Previous analyses of complexes of 40S ribosomal subunits with the hepatitis C virus (HCV) internal ribosome entry site (IRES) have revealed contacts made by the IRES with ribosomal proteins. Here, using chemical probing, we show that the HCV IRES also contacts the backbone and bases of the CCC triplet in the 18S ribosomal RNA (rRNA) expansion segment 7. These contacts presumably provide interpl...
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عنوان ژورنال:
دوره 5 شماره
صفحات -
تاریخ انتشار 2009