Identification of N-phenyl-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4
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- 作者：Qian Zhao ; Liying Ma ; Shibo Jiang ; Hong Lu ; Shuwen Liu ; Yuxian He ; Nathan Strick ; Nouri Neamati and Asim Kumar Debnath
- 关键词：HIV-1 entry ; Inhibition ; CD4– ; gp120 interaction ; Cell– ; cell fusion ; Virus– ; cell fusion
- 刊名：Virology
- 出版年：2005
- 出版时间：2005
- 年：2005
- 卷：339
- 期：2
- 页码：213-225
- 全文大小：372 K
文摘
We have identified two N-phenyl-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamide analogs as a novel class of human immunodeficiency virus type 1 (HIV-1) entry inhibitors that block the gp120–CD4 interaction, using database screening techniques. The lead compounds, NBD-556 and NBD-557, are small molecule organic compounds with drug-like properties. These compounds showed potent cell fusion and virus–cell fusion inhibitory activity at low micromolar levels. A systematic study showed that these compounds target viral entry by inhibiting the binding of HIV-1 envelope glycoprotein gp120 to the cellular receptor CD4 but did not inhibit reverse transcriptase, integrase, or protease, indicating that they do not target the later stages of the HIV-1 life cycle to inhibit HIV-1 infection. These compounds were equally potent inhibitors of both X4 and R5 viruses tested in CXCR4 and CCR5 expressing cell lines, respectively, indicating that their anti-HIV-1 activity is not dependent on the coreceptor tropism of the virus. A surface plasmon resonance study, which measures binding affinity, clearly demonstrated that these compounds bind to unliganded HIV-1 gp120 but not to the cellular receptor CD4. NBD-556 and NBD-557 were active against HIV-1 laboratory-adapted strains including an AZT-resistant strain and HIV-1 primary isolates, indicating that these compounds can potentially be further modified to become potent HIV-1 entry inhibitors.