title: 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.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA. blair.wade@gene.com
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Lynn
authors.initials: L
authors.lastname: Jackson
authors.forename: Judith
authors.initials: J
authors.lastname: Jimenez
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Peng
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Jason
authors.initials: J
authors.lastname: Isaacson
authors.forename: Scott L
authors.initials: SL
authors.lastname: Butler
authors.forename: Alex
authors.initials: A
authors.lastname: Chu
authors.forename: Joanne
authors.initials: J
authors.lastname: Graham
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Malfait
authors.forename: Micky
authors.initials: M
authors.lastname: Tortorella
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D015153:Blotting, Western; D003521:Cyclopropanes; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004274:DNA, Recombinant / Q000096:biosynthesis / Q000235:genetics; D024881:Drug Resistance, Bacterial; D016655:HIV Core Protein p24 / Q000032:analysis / Q000096:biosynthesis; D019302:HIV Envelope Protein gp160 / Q000096:biosynthesis* / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: C524481:2-(1-(2-(2,3-dihydro-1-benzofuran-5-yl)ethyl)piperidin-3-yl)-2,2-diphenylacetamide; D000480:Alkynes; D019380:Anti-HIV Agents; D044482:Benzeneacetamides; D048588:Benzoxazines; D003521:Cyclopropanes; D004274:DNA, Recombinant; D016655:HIV Core Protein p24; D019302:HIV Envelope Protein gp160; D010880:Piperidines; C098320:efavirenz