Abstract |
Human immunodeficiency virus type 1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Therefore, IN inhibitors are being sought for chemotherapy against AIDS. We had previously identified a series of salicylhydrazides as potent inhibitors of IN in vitro (Neamati, N.; et al. J. Med. Chem. 1998, 41, 3202-3209.). Herein, we report the design, synthesis, and antiviral activity of three novel mercaptosalicylhydrazide ( MSH) derivatives. MSHs were effective against the IN catalytic core domain and inhibited IN binding to HIV LTR DNA. They also inhibited catalytic activities of IN in IN- DNA preassembled complexes. Site-directed mutagenesis and molecular modeling studies suggest that MSHs bind to cysteine 65 and chelate Mg(2+) at the active site of HIV-1 IN. Contrary to salicylhydrazides, the MSHs are 300-fold less cytotoxic and exhibit antiviral activity. They are also active in Mg(2+)-based assays, while IN inhibition by salicylhydrazides is strictly Mn(2+)-dependent. Additionally, in target and cell-based assays, the MSHs have no detectable effect on other retroviral targets, including reverse transcriptase, protease, and virus attachment, and exhibit no detectable activity against human topoisomerases I and II at concentrations that effectively inhibit IN. These data suggest that MSHs are selective inhibitors of HIV-1 IN and may serve as leads for antiviral therapeutics.
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Authors | Nouri Neamati, Zhaiwei Lin, Rajeshri G Karki, Ann Orr, Kiriana Cowansage, Dirk Strumberg, Godwin C G Pais, Johannes H Voigt, Marc C Nicklaus, Heather E Winslow, He Zhao, Jim A Turpin, Jizu Yi, Anna Marie Skalka, Terrence R Burke Jr, Yves Pommier |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 45
Issue 26
Pg. 5661-70
(Dec 19 2002)
ISSN: 0022-2623 [Print] United States |
PMID | 12477350
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antiviral Agents
- Cations, Divalent
- Chelating Agents
- HIV Integrase Inhibitors
- Hydrazines
- Salicylates
- Sulfhydryl Compounds
- Topoisomerase I Inhibitors
- Topoisomerase II Inhibitors
- Manganese
- DNA
- Magnesium
- Cysteine
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Topics |
- Antiviral Agents
(chemical synthesis, chemistry, pharmacology)
- Binding Sites
- Catalytic Domain
- Cations, Divalent
- Cell Line
- Chelating Agents
(chemical synthesis, chemistry, pharmacology)
- Cysteine
(chemistry)
- DNA
(chemistry)
- HIV Integrase Inhibitors
(chemical synthesis, chemistry, pharmacology)
- HIV-1
(drug effects)
- Humans
- Hydrazines
(chemical synthesis, chemistry, pharmacology)
- Magnesium
- Manganese
- Models, Molecular
- Salicylates
(chemical synthesis, chemistry, pharmacology)
- Structure-Activity Relationship
- Sulfhydryl Compounds
(chemical synthesis, chemistry, pharmacology)
- Topoisomerase I Inhibitors
- Topoisomerase II Inhibitors
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