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

doi:10.1016/j.chembiol.2007.06.003

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

^*Korrespondierende/r Autor/-in für diese Arbeit

51 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Chemistry and Biology
Jahrgang	14
Ausgabenummer	7
Seiten (von - bis)	804-812
Seitenumfang	9
ISSN	1074-5521
DOIs	https://doi.org/10.1016/j.chembiol.2007.06.003
Publikationsstatus	Veröffentlicht - 30.07.2007

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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.).

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10.1016/j.chembiol.2007.06.003

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title = "Aptamer Displacement Identifies Alternative Small-Molecule Target Sites that Escape Viral Resistance",

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.",

author = "Satoko Yamazaki and Lu Tan and G{\"u}nter Mayer and Hartig, \{J{\"o}rg S.\} and Song, \{Jin Na\} and Sandra Reuter and Tobias Restle and Laufer, \{Sandra D.\} and Dina Grohmann and Kr{\"a}usslich, \{Hans Georg\} and J{\"u}rgen Bajorath and Michael Famulok",

note = "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.). ",

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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 - https://www.scopus.com/pages/publications/34447574625

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 -

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

Abstract

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