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Identification of a methylated oligoribonucleotide as a potent inhibitor of HIV-1 reverse transcription complex.

Abstract：

:Upon HIV-1 infection of a target cell, the viral reverse transcriptase (RT) copies the genomic RNA to synthesize the viral DNA. The genomic RNA is within the incoming HIV-1 core where it is coated by molecules of nucleocapsid (NC) protein that chaperones the reverse transcription process. Indeed, the RT chaperoning properties of NC extend from the initiation of cDNA synthesis to completion of the viral DNA. New and effective drugs against HIV-1 continue to be required, which prompted us to search for compounds aimed at inhibiting NC protein. Here, we report that the NC chaperoning activity is extensively inhibited in vitro by small methylated oligoribonucleotides (mODN). These mODNs were delivered intracellularly using a cell-penetrating-peptide and found to impede HIV-1 replication in primary human cells at nanomolar concentrations. Extensive analysis showed that viral cDNA synthesis was severely impaired by mODNs. Partially resistant viruses with mutations in NC and RT emerged after months of passaging in cell culture. A HIV-1 molecular clone (NL4.3) bearing these mutations was found to replicate at high concentrations of mODN, albeit with a reduced fitness. Small, methylated ODNs such as mODN-11 appear to be a new type of highly potent inhibitor of HIV-1.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Grigorov B,Bocquin A,Gabus C,Avilov S,Mély Y,Agopian A,Divita G,Gottikh M,Witvrouw M,Darlix JL

doi

10.1093/nar/gkr117

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

5586-96

issue

13

eissn

0305-1048

issn

1362-4962

pii

gkr117

journal_volume

39

pub_type

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