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Antimicrobial Agents and Chemotherapy, October 2007, p. 3554-3561, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00643-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of UK-201844, a Novel Inhibitor That Interferes with Human Immunodeficiency Virus Type 1 gp160 Processing{triangledown}

Wade S. Blair,1* Joan Cao,1 Lynn Jackson,1 Judith Jimenez,1 Qinghai Peng,1 Hua Wu,1 Jason Isaacson,1 Scott L. Butler,1 Alex Chu,1 Joanne Graham,1 Anne-Marie Malfait,2 Micky Tortorella,2 and Amy K. Patick1

Pfizer Global Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, California 92121,1 Pfizer Global Research and Development, St. Louis Laboratories, Chesterfield, Missouri 630172

Received 15 May 2007/ Returned for modification 22 June 2007/ Accepted 17 July 2007

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.

* Corresponding author. Present address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: (650) 467-5290. Fax: (650) 467-7565. E-mail: blair.wade{at}gene.com

{triangledown} Published ahead of print on 23 July 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3554-3561, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00643-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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