Aptamer Displacement Identifies Alternative Small-Molecule Target Sites that Escape Viral Resistance

Satoko Yamazaki, Lu Tan, Günter Mayer, Jörg S. Hartig, Jin Na Song, Sandra Reuter, Tobias Restle, Sandra D. Laufer, Dina Grohmann, Hans Georg Kräusslich, Jürgen Bajorath*, Michael Famulok

*Corresponding author for this work
48 Citations (Scopus)


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 languageEnglish
JournalChemistry and Biology
Issue number7
Pages (from-to)804-812
Number of pages9
Publication statusPublished - 30.07.2007


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