TY - JOUR
T1 - Aptamer Displacement Identifies Alternative Small-Molecule Target Sites that Escape Viral Resistance
AU - Yamazaki, Satoko
AU - Tan, Lu
AU - Mayer, Günter
AU - Hartig, Jörg S.
AU - Song, Jin Na
AU - Reuter, Sandra
AU - Restle, Tobias
AU - Laufer, Sandra D.
AU - Grohmann, Dina
AU - Kräusslich, Hans Georg
AU - Bajorath, Jürgen
AU - Famulok, Michael
N1 - Funding Information:
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.).
PY - 2007/7/30
Y1 - 2007/7/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34447574625&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2007.06.003
DO - 10.1016/j.chembiol.2007.06.003
M3 - Journal articles
C2 - 17656317
AN - SCOPUS:34447574625
SN - 1074-5521
VL - 14
SP - 804
EP - 812
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 7
ER -
