title: Interaction of oligonucleotides conjugated to substituted chromones and coumarins with HIV-1 reverse transcriptase.
abstract: Ten different pyranone-related substituents (chromones or coumarins) were covalently linked to the 5' end of various oligonucleotides (ODN). The interaction of these compounds with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) was analyzed. A different behavior was found to depend on the structure of the oligonucleotide derivatives. Some compounds activated the enzyme at relatively low concentrations (0.1-0.5 microM), followed by an inhibition of the activity at higher concentrations (5-20 microM), whereas others behave just as inhibitors. Because the presence of some coumarin or chromone derivatives conjugated to ODNs enhanced the interaction with the reverse transcriptase, we analyzed the capacity of such ODN derivatives to be used as primers. The introduction of substituent I, a chromone derivative, the 2-[(3-(aminopropyl)amino]-8-isopropyl-5-methyl-4-oxo-4H-1-benzopyran-3-c arbaldehyde], and II, a coumarin derivative, the 1-(3-aminopropoxy)-2-ethyl-3H-naphto[2,1-b]pyran-3-one, into the 5' end of a noncomplementary ODN allowed these compounds to be used as primers. In the case of complementary primers, the presence of conjugated derivatives enhanced the affinity with Km values that were two to three orders of magnitude lower than that of a complementary primer of the same length. After addition of a ddT-unit to the 3'-terminal end of the ODN, some of these primers became very effective inhibitors of RT with Ki values in the nanomolar range.
authors.affiliation: Novosibirsk Institute of Bioorganic Chemistry, Siberian Division of the Russian Academy of Sciences.
authors.forename: I V
authors.initials: IV
authors.lastname: Martyanov
authors.forename: O D
authors.initials: OD
authors.lastname: Zakharova
authors.forename: E
authors.initials: E
authors.lastname: Sottofattori
authors.forename: D V
authors.initials: DV
authors.lastname: Pyshnyi
authors.forename: E Y
authors.initials: EY
authors.lastname: Yurchenko
authors.forename: P
authors.initials: P
authors.lastname: Babbi
authors.forename: M
authors.initials: M
authors.lastname: Mazzei
authors.forename: A
authors.initials: A
authors.lastname: Balbi
authors.forename: M L
authors.initials: ML
authors.lastname: Andreola
authors.forename: S
authors.initials: S
authors.lastname: Litvak
authors.forename: L
authors.initials: L
authors.lastname: Tarrago-Litvak
authors.forename: G A
authors.initials: GA
authors.lastname: Nevinsky
mesh_terms: D002867:Chromones / Q000737:chemistry / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D002867:Chromones; D003374:Coumarins; D009841:Oligonucleotides; D054303:HIV Reverse Transcriptase