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

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

  • Antimicrob Agents Chemother. 2007 Oct;51(10):3554-61. doi: 10.1128/AAC.00643-07.
Wade S Blair 1 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
Affiliations

Affiliation

  • 1 Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA. blair.wade@gene.com
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.

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