title: In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor.
abstract: XM323 represents a novel class of potent inhibitors of human immunodeficiency virus (HIV) protease. In vitro studies have shown that inhibition of this enzyme translates into potent inhibition of replication of HIV type 1 (HIV-1) and HIV-2. The inhibition of virus replication was assessed with three assays designed to measure the production of infectious virus, viral RNA, or p24 antigen. The production of mature infectious virions was measured with a yield reduction assay. By this assay, several strains and isolates of HIV-1 and HIV-2 were shown to be susceptible to XM323 in two lymphoid cell lines (MT-2 and H9) and in normal peripheral blood mononuclear cells, with a concentration required for 90% inhibition (IC90) of 0.12 +/- 0.04 microM (mean +/- standard deviation). The production of HIV-1(RF) RNA was measured with an RNA hybridization-capture assay. With this assay, XM323 was shown to be a potent inhibitor of HIV-1(RF) replication, with an IC90 of 0.063 +/- 0.032 microM. A third measure of virus replication, the production of p24 viral antigen, an essential protein component of the virion, was determined with the AIDS Clinical Trial Group-Department of Defense peripheral blood mononuclear cell consensus assay. This assay was used for expanded testing of XM323 against 28 clinical isolates and laboratory strains of HIV-1. XM323 was shown to be equally effective against zidovudine-susceptible and zidovudine-resistant isolates of HIV-1, with an overall IC90 of 0.16 +/- 0.06 microM.
authors.affiliation: Du Pont Merck Pharmaceutical Company, Glenolden, Pennsylvania 19036.
authors.forename: M J
authors.initials: MJ
authors.lastname: Otto
authors.forename: C D
authors.initials: CD
authors.lastname: Reid
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: P Y
authors.initials: PY
authors.lastname: Lam
authors.forename: H
authors.initials: H
authors.lastname: Scarnati
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: M M
authors.initials: MM
authors.lastname: Rayner
authors.forename: D L
authors.initials: DL
authors.lastname: Winslow
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000382:microbiology; D009693:Nucleic Acid Hybridization; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; C085886:XM 323