title: Chain-terminating dinucleoside tetraphosphates are substrates for DNA polymerization by human immunodeficiency virus type 1 reverse transcriptase with increased activity against thymidine analogue-resistant mutants.
abstract: Nucleoside reverse transcriptase inhibitors are an important class of drugs for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Resistance to these drugs is often the result of mutations that increase the transfer of chain-terminating nucleotides from blocked DNA termini to a nucleoside triphosphate acceptor, resulting in the generation of an unblocked DNA chain and synthesis of a dinucleoside polyphosphate containing the chain-terminating deoxynucleoside triphosphate analogue. We have synthesized and purified several dinucleoside tetraphosphates (ddAp4ddA, ddCp4ddC, ddGp4ddG, ddTp4ddT, Ap4ddG, 2'(3')-O-(N-methylanthraniloyl)-Ap4ddG, and AppNHppddG) and show that these compounds can serve as substrates for DNA chain elongation and termination resulting in inhibition of DNA synthesis. Thymidine analogue-resistant mutants of reverse transcriptase are up to 120-fold more sensitive to inhibition by these compounds than is wild-type enzyme. Drugs based on the dinucleoside tetraphosphate structure could delay or prevent the emergence of mutants with enhanced primer unblocking activity. In addition, such drugs could suppress the resistance phenotype of mutant HIV-1 that is present in individuals infected with resistant virus.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, P.O. Box 016129, Miami, FL 33101-6129, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Meyer
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Matsuura
authors.forename: Walter A
authors.initials: WA
authors.lastname: Scott
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D015224:Dideoxynucleosides / Q000737:chemistry; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis / Q000378:metabolism*; D024882:Drug Resistance, Viral; D024202:Electrophoretic Mobility Shift Assay; D054303:HIV Reverse Transcriptase / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004279:DNA, Viral; D015224:Dideoxynucleosides; D015226:Dinucleoside Phosphates; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013936:Thymidine