Open AccessIdentification and Characterization of UK-201844, a Novel Inhibitor That Interferes with Human Immunodeficiency Virus Type 1 gp160 Processing
Author(s) -
Wade Blair,
Joan Cao,
Lynn Jackson,
Judith Jiménez,
Qinghai Peng,
Hua Wu,
Jason Isaacson,
Scott L. Butler,
Alex Chu,
Joanne P. Graham,
AnneMarie Malfait,
Micky D. Tortorella,
Amy K. Patick
Publication year - 2007
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00643-07
Subject(s) - virology , virus , vesicular stomatitis virus , glycoprotein , biology , lentivirus , viral envelope , heterologous , in vitro , cell culture , entry inhibitor , v3 loop , viral entry , viral replication , microbiology and biotechnology , peptide sequence , viral disease , gene , biochemistry , genetics
More than 106 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 μM, 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.