Abstract
Aptamers targeting reverse transcriptase (RT) from HIV-1 inhibit viral replication in vitro, presumably by competing with binding of the primer/template complex. This site is not targeted by the currently available small-molecule anti-HIV-1 RT inhibitors. We have identified SY-3E4, a small-molecule inhibitor of HIV-1 RT, by applying a screening assay that utilizes a reporter-ribozyme regulated by the anti-HIV-1 RT aptamer. SY-3E4 displaces the aptamer from the protein, selectively inhibits DNA-dependent, but not RNA-dependent, polymerase activity, and inhibits the replication of both the wild-type virus and a multidrug-resistant strain. Analysis of available structural data of HIV-1 and HIV-2 RTs rationalizes many of the observed characteristics of the inhibitory profiles of SY-3E4 and the aptamer and suggests a previously not considered region in these RTs as a target for antiviral therapy. Our study reveals unexplored ways for rapidly identifying alternative small-molecule target sites in proteins and illustrates strategies for overcoming resistance-conferring mutations with small molecules.
| Original language | English |
|---|---|
| Journal | Chemistry and Biology |
| Volume | 14 |
| Issue number | 7 |
| Pages (from-to) | 804-812 |
| Number of pages | 9 |
| ISSN | 1074-5521 |
| DOIs | |
| Publication status | Published - 30.07.2007 |
Funding
We thank A. Schmitz and the members of the Famulok lab for helpful discussions, K. Rotscheidt for technical assistance, and H. Walter (Erlangen) for a plasmid carrying the multidrug-resistant HIV-1 sequence. This work was supported by grants from the Sonderforschungsbereich 704 (to M.F. and J.B.), the Sonderforschungsbereich 544 (to H.-G.K.), the Deutsche Forschungsgemeinschaft (to M.F.), the Fonds der Chemischen Industrie (to M.F.), the European Community (to T.R.), and the Deutscher Akademischer Austauschdienst DAAD (to S.Y.).
