Abstract:
:We have previously shown that styrylquinolines (SQLs) are integrase inhibitors in vitro. They compete with the long terminal repeat substrate for integrase. Here, we describe the cellular mode of action of these molecules. We show that SQLs do not interfere with virus entry. In fact, concentrations of up to 20 times the 50% inhibitory concentration did not inhibit cell-to-cell fusion or affect the interaction between GP120 and CD4 in vitro. Moreover, the pseudotype of the retrovirus envelope did not affect drug activity. Quantitative reverse transcription PCR experiments showed that SQLs do not inhibit the entry of the genomic RNA. In contrast, the treatment of human immunodeficiency virus type 1-infected cells with SQLs reduced the amount of the late cDNA, suggesting for the first time that integrase targeting molecules may affect the accumulation of DNA during reverse transcription. The cellular target of SQLs was confirmed by the appearance of mutations in the integrase gene when viruses were grown in the presence of increasing concentrations of SQLs. Finally, these mutations led to SQL-resistant viruses when introduced into the wild-type sequence. In contrast, SQLs were fully active against reverse transcriptase inhibitor- and diketo acid-resistant viruses, positioning SQLs as a second group of anti-integrase compounds.
journal_name
J Viroljournal_title
Journal of virologyauthors
Bonnenfant S,Thomas CM,Vita C,Subra F,Deprez E,Zouhiri F,Desmaële D,D'Angelo J,Mouscadet JF,Leh Hdoi
10.1128/JVI.78.11.5728-5736.2004subject
Has Abstractpub_date
2004-06-01 00:00:00pages
5728-36issue
11eissn
0022-538Xissn
1098-5514pii
78/11/5728journal_volume
78pub_type
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