Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing.

Abstract

More than 10(6) compounds were evaluated in a human immunodeficiency virus type 1 (HIV-1) high-throughput antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (UK-201844). UK-201844 exhibited antiviral activity against HIV-1 NL4-3 in MT-2 and PM1 cells, with 50% effective concentrations of 1.3 and 2.7 microM, respectively, but did not exhibit measurable antiviral activity against the closely related HIV-1 IIIB laboratory strain. UK-201844 specifically inhibited the production of infectious virions packaged with an HIV-1 envelope (Env), but not HIV virions packaged with a heterologous Env (i.e., the vesicular stomatitis virus glycoprotein), suggesting that the compound targets HIV-1 Env late in infection. Subsequent antiviral assays using HIV-1 NL4-3/IIIB chimeric viruses showed that HIV-1 Env sequences were critical determinants of UK-201844 susceptibility. Consistent with this, in vitro resistant-virus studies revealed that amino acid substitutions in HIV-1 Env are sufficient to confer resistance to UK-201844. Western analysis of HIV Env proteins expressed in transfected cells or in isolated virions showed that UK-201844 inhibited HIV-1 gp160 processing, resulting in the production of virions with nonfunctional Env glycoproteins. Our results demonstrate that UK-201844 represents the prototype for a unique HIV-1 inhibitor class that directly or indirectly interferes with HIV-1 gp160 processing.

• Authors: Wade S Blair, Joan Cao, Lynn Jackson, Judith Jimenez, Qinghai Peng, Hua Wu, Jason Isaacson, Scott L Butler, Alex Chu, Joanne Graham, Anne-Marie Malfait, Micky Tortorella, Amy K Patick
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 10 Pg. 3554-61 (Oct 2007) ISSN: 0066-4804 [Print] United States
• PMID: 17646410 (Publication Type: Journal Article)

Chemical References

• 2-(1-(2-(2,3-dihydro-1-benzofuran-5-yl)ethyl)piperidin-3-yl)-2,2-diphenylacetamide
• Alkynes
• Anti-HIV Agents
• Benzeneacetamides
• Benzoxazines
• Cyclopropanes
• DNA, Recombinant
• HIV Core Protein p24
• HIV Envelope Protein gp160
• Piperidines
• efavirenz

Topics

• Alkynes
• Anti-HIV Agents (pharmacology)
• Benzeneacetamides (pharmacology)
• Benzoxazines (pharmacology)
• Blotting, Western
• Cyclopropanes
• Cytopathogenic Effect, Viral (drug effects)
• DNA, Recombinant (biosynthesis, genetics)
• Drug Resistance, Bacterial
• HIV Core Protein p24 (analysis, biosynthesis)
• HIV Envelope Protein gp160 (biosynthesis, drug effects)
• HIV-1 (drug effects)
• HeLa Cells
• Humans
• Piperidines (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• Virus Replication (drug effects)