Abstract:
:Human La protein has been implicated in facilitating internal ribosome entry site (IRES)-mediated translation of hepatitis C virus (HCV). Earlier, we demonstrated that the RNA recognition motif (RRM) encompassing residues 112 to 184 of La protein [La (112-184)] interacts with the HCV IRES near the initiator AUG codon. A synthetic peptide, LaR2C (24-mer), derived from La RRM (112-184), retains RNA binding ability, competes with La protein binding to the HCV IRES, and inhibits translation. The peptide interferes with the assembly of 48S complexes, resulting in the accumulation of preinitiation complexes that are incompetent for the 60S ribosomal subunit joining. Here, nuclear magnetic resonance spectroscopy of the HCV IRES-bound peptide complex revealed putative contact points, mutations that showed reduced RNA binding and translation inhibitory activity. The residues responsible for RNA recognition were found to form a turn in the RRM (112-184) structure. A 7-mer peptide comprising this turn showed significant translation inhibitory activity. The bound structure of the peptide inferred from transferred nuclear Overhauser effect experiments suggests that it is a beta turn. This conformation is significantly different from that observed in the free RRM (112-184) NMR structure, suggesting paths toward a better-stabilized mimetic peptide. Interestingly, addition of hexa-arginine tag enabled the peptide to enter Huh7 cells and showed inhibition of HCV IRES function. More importantly, the peptide significantly inhibited replication of the HCV monocistronic replicon. Elucidation of the structural determinant of the peptide provides a basis for developing small peptidomimetic structures as potent anti-HCV therapeutics.
journal_name
J Viroljournal_title
Journal of virologyauthors
Mondal T,Ray U,Manna AK,Gupta R,Roy S,Das Sdoi
10.1128/JVI.00924-08subject
Has Abstractpub_date
2008-12-01 00:00:00pages
11927-38issue
23eissn
0022-538Xissn
1098-5514pii
JVI.00924-08journal_volume
82pub_type
杂志文章abstract::Although recombinant human adenovirus (HAV)-based vectors offer several advantages for somatic gene therapy and vaccination over other viral vectors, it would be desirable to develop alternative vectors with prolonged expression and decreased toxicity. Toward this objective, a replication-defective bovine adenovirus t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.11.9137-9144.1999
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.61.4.1244-1247.1987
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.12.1.49-57.1973
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.3.1432-1441.1992
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.11.7570-7574.1994
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.49.2.319-324.1984
更新日期:1984-02-01 00:00:00
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journal_title:Journal of virology
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doi:10.1128/JVI.3.5.506-512.1969
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journal_title:Journal of virology
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.10.5914-5923.1992
更新日期:1992-10-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.2.1013-1018.1997
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.44.1.269-275.1982
更新日期:1982-10-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.2.784-795.2000
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.3.2425-2435.1997
更新日期:1997-03-01 00:00:00