title: Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors.
abstract: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is potently inhibited by a structurally diverse group of nonnucleoside compounds. These include pyridinone derivatives, tetrahydroimadazo[4,5,1-j,k][1,4]-benzodiazepin-2(1H)-one and -thione, and BI-RG-587 (nevirapine). The compounds act noncompetitively, by an unknown mechanism, with respect to template-primer and nucleotide substrates. Despite a high degree of similarity between the HIV-1 and HIV-2 RTs, the HIV-2 enzyme is totally insensitive to these inhibitors. Using a novel method for joining DNA sequences, we have exploited this difference between the two enzymes to identify the regions of the RT that contribute to the compounds' inhibitory activities. The relative in vitro sensitivities of HIV-1/HIV-2 chimeric and site-specific mutant enzymes were determined. Sensitivity to inhibition was largely, though not exclusively, dependent upon the RT region defined by amino acid residues 176 to 190, with specific contributions by residues 181 and 188. The region defined by residues 101 to 106 was found to functionally interact with the domain from 155 to 217. In addition, the functional equivalence of the three inhibitor groups was shown.
authors.affiliation: Department of Virus and Cell Biology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004.
authors.forename: J H
authors.initials: JH
authors.lastname: Condra
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: L
authors.initials: L
authors.lastname: Gotlib
authors.forename: D J
authors.initials: DJ
authors.lastname: Graham
authors.forename: A J
authors.initials: AJ
authors.lastname: Schlabach
authors.forename: J A
authors.initials: JA
authors.lastname: Wolfgang
authors.forename: R J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: V V
authors.initials: VV
authors.lastname: Sardana
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019829:Nevirapine; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors
chemical_list: D000998:Antiviral Agents; D001381:Azepines; D001583:Benzoxazoles; D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; C070357:L 697639; C067413:R-82913; D019829:Nevirapine; D054303:HIV Reverse Transcriptase