title: A novel mechanism for inhibition of HIV-1 reverse transcriptase.
abstract: The human immunodeficiency virus (HIV) epidemic is an important medical problem. Although combination drug regimens have produced dramatic decreases in viral load, current therapies do not provide a cure for HIV infection. We have used structure-based design and combinatorial medicinal chemistry to identify potent and selective HIV-1 reverse transcriptase (RT) inhibitors that may work by a mechanism distinct from that of current HIV drugs. The most potent of these compounds (compound 4, 2-naphthalenesulfonic acid, 4-hydroxy-7-[[[[5-hydroxy-6-[(4-cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]carbonyl]amino]-3-[(4-cinnamylphenyl)azo], disodium salt) has an IC(50) of 90 nM for inhibition of polymerase chain extension, a K(d) of 40 nM for inhibition of DNA-RT binding, and an IC(50) of 25-100 nM for inhibition of RNaseH cleavage. The parent compound (1) was as effective against 10 nucleoside and non-nucleoside resistant HIV-1 RT mutants as it was against the wild-type enzyme. Compound 4 inhibited HIV-1 RT and murine leukemia virus (MLV) RT, but it did not inhibit T(4) DNA polymerase, T(7) DNA polymerase, or the Klenow fragment at concentrations up to 200 nM. Finally, compound 4 protected cells from HIV-1 infection at a concentration more than 40 times lower than the concentration at which it caused cellular toxicity.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, 513 Parnassus Ave, Box 0446, San Francisco, CA 94143-0446, USA.
authors.forename: A Geoffrey
authors.initials: AG
authors.lastname: Skillman
authors.forename: Karl W
authors.initials: KW
authors.lastname: Maurer
authors.forename: Diana C
authors.initials: DC
authors.lastname: Roe
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Stauber
authors.forename: Dolan
authors.initials: D
authors.lastname: Eargle
authors.forename: Todd J A
authors.initials: TJ
authors.lastname: Ewing
authors.forename: Angelika
authors.initials: A
authors.lastname: Muscate
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
authors.forename: Maxine V
authors.initials: MV
authors.lastname: Medaglia
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Edward
authors.initials: E
authors.lastname: Arnold
authors.forename: Hong Qiang
authors.initials: HQ
authors.lastname: Gao
authors.forename: Robert
authors.initials: R
authors.lastname: Buckheit
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: George L
authors.initials: GL
authors.lastname: Kenyon
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016914:Ribonuclease H / Q000378:metabolism
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H