HIV integrase inhibitors with nucleobase scaffolds: Discovery of a highly potent anti-HIV agent

被引：68

作者：

Nair, V ^{[1
]}

Chi, G

Ptak, R

Neamati, N

机构：

[1] Univ Georgia, Ctr Drug Discovery, Athens, GA 30602 USA

[2] Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA

[3] So Res Inst, Infect Dis Res Dept, Frederick, MD 21701 USA

[4] Univ So Calif, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 02期

关键词：

D O I：

10.1021/jm0508890

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new beta-diketo acid that is a powerful inhibitor of both the 3'-processing and strand transfer steps of HIV-1 integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIVTEKI and HIV-1(NL4-3) replication in PBMC (TI > 4,000 and > 10,000, respectively).

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页码：445 / 447

页数：3

相关论文

共 28 条

[1] HIV-1 integrase: Structural organization, conformational changes, and catalysis [J].

Asante-Appiah, E ;

Skalka, AM .

ADVANCES IN VIRUS RESEARCH, VOL 52, 1999, 52 :351-369

[2] Small-molecule HIV-1 integrase inhibitors: the 2001-2002 update [J].

Dayam, R ;

Neamati, N .

CURRENT PHARMACEUTICAL DESIGN, 2003, 9 (22) :1789-1802

[3] New approaches toward anti-HIV chemotherapy [J].

De Clercq, E .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) :1297-1313

[4] Strategies in the design of antiviral drugs [J].

De Clercq, E .

NATURE REVIEWS DRUG DISCOVERY, 2002, 1 (01) :13-25

[5] In search of a selective antiviral chemotherapy [J].

DeClercq, E .

CLINICAL MICROBIOLOGY REVIEWS, 1997, 10 (04) :674-+

[6] CRYSTAL-STRUCTURE OF THE CATALYTIC DOMAIN OF HIV-1 INTEGRASE - SIMILARITY TO OTHER POLYNUCLEOTIDYL TRANSFERASES [J].

DYDA, F ;

HICKMAN, AB ;

JENKINS, TM ;

ENGELMAN, A ;

CRAIGIE, R ;

DAVIES, DR .

SCIENCE, 1994, 266 (5193) :1981-1986

[7] HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase [J].

Espeseth, AS ;

Felock, P ;

Wolfe, A ;

Witmer, M ;

Grobler, J ;

Anthony, N ;

Egbertson, M ;

Melamed, JY ;

Young, S ;

Hamill, T ;

Cole, JL ;

Hazuda, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (21) :11244-11249

[8] HIV integrase structure and function [J].

Esposito, D ;

Craigie, R .

ADVANCES IN VIRUS RESEARCH, VOL 52, 1999, 52 :319-333

[9] THE HUMAN IMMUNODEFICIENCY VIRUS - INFECTIVITY AND MECHANISMS OF PATHOGENESIS [J].

FAUCI, AS .

SCIENCE, 1988, 239 (4840) :617-622

[10] HIV-1: Fifteen proteins and an RNA [J].

Frankel, AD ;

Young, JAT .

ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 :1-25