title: Impeded progression of Friend disease in mice by an inhibitor of retroviral proteases.
abstract: The protease of the human immunodeficiency virus type 1 (HIV-1) is essential for the processing of GAG and POL polyproteins and maturation of the virus particles. Using recombinant protease and a truncated GAG polyprotein as substrate, we developed a Western blot assay for the evaluation of inhibitors of the enzyme. Two statine-based inhibitors of the enzyme, KH161 and KH164, were effective in blocking the replication of HIV-1 in acutely infected human T4 lymphoid cells, with potency approaching that of zidovudine (ZDV) when tested in parallel. In chronically infected cells, the production of infectious virus was inhibited by KH161 and KH164, while ZDV was ineffective. Both KH161 and KH164 were also active as antivirals against the replication of murine leukemia virus (MLV) in cultured mouse cells. In an animal model of a murine retroviral disease, KH164 was shown to inhibit in a dose-dependent manner the progression of the disease induced by Friend virus complex (a mixture of Friend MLV and spleen focus-forming virus). The results suggest that the progression of the acquired immune deficiency syndrome (AIDS) may be impeded by inhibitors of HIV-1 protease.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285.
authors.forename: M H
authors.initials: MH
authors.lastname: Lai
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.forename: V
authors.initials: V
authors.lastname: Wroblewski
authors.forename: A G
authors.initials: AG
authors.lastname: Dee
authors.forename: N
authors.initials: N
authors.lastname: Margolin
authors.forename: C
authors.initials: C
authors.lastname: Vlahos
authors.forename: B
authors.initials: B
authors.lastname: Bowdon
authors.forename: R
authors.initials: R
authors.lastname: Buckheit
authors.forename: J
authors.initials: J
authors.lastname: Colacino
authors.forename: K Y
authors.initials: KY
authors.lastname: Hui
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002460:Cell Line; D004195:Disease Models, Animal; D005622:Friend murine leukemia virus / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data
chemical_list: D000596:Amino Acids; D017320:HIV Protease Inhibitors; C013165:statine