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.