title: Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives.
abstract: Dicamphanoyl khellactone (DCK) is a coumarin derivative that can potently inhibit HIV-1 replication. DCK does not inhibit RNA-dependent DNA synthesis. However, an HIV reverse transcriptase (RT) inhibitor-resistant strain, HIV-1/RTMDR1, is resistant to DCK. Thus, it is possible that HIV-1 RT is the target of DCK. To test this possibility, DCK-resistant viruses were selected in the presence of DCK. Our results indicate that a single amino acid mutation, E138K in HIV-1 RT, is sufficient to confer DCK resistance. Interestingly, a DCK derivative, 3'R,4'R-Di-O-(-)-camphanoyl-2-ethyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP8), is effective against HIV-1/RTMDR1. However, the DCK-escape virus carrying the E138K mutation remains resistant to DCP8. Since DCK did not inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT when using poly-rA or poly-rC as template, we evaluated the effect of DCK on the DNA-dependent DNA polymerase activity of HIV-1 RT. Our results indicate that DCK can inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT. In conclusion, DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity. In contrast, DCK did not significantly affect the RNA-dependent DNA polymerase activity when poly-rA or poly-rC was used as templates. An E138K mutation in the non-nucleoside RT inhibitors (NNRTIs) binding pocket of HIV-1 RT confers resistance to DCK and its chromone derivative, DCP8.
authors.affiliation: Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, LaSalle Street Extension, Durham, NC 27710, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Xiong
authors.initials: X
authors.lastname: Yuan
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: Chin Ho
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002164:Camphor / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; D019380:Anti-HIV Agents; D003374:Coumarins; D007783:Lactones; D018894:Reverse Transcriptase Inhibitors; D002164:Camphor