title: New class of HIV integrase inhibitors that block viral replication in cell culture.
abstract: BACKGROUND
  To improve the existing combination therapies of infection with the human immunodeficiency virus (HIV) and to cope with virus strains that are resistant to multiple drugs, we initiated a search for effective inhibitors of HIV integrase, the enzyme responsible for inserting the viral cDNA into the host cell chromosome.
  
  
  RESULTS
  We have now identified a series of 5H-pyrano[2,3-d:-6,5-d']dipyrimidines that block the replication of various strains of HIV-1 and HIV-2. The most potent congener, 5-(4-nitrophenyl)-2,8-dithiol-4,6-dihydroxy-5H-pyrano[2,3-d:-6,5-d']dipyrimidine (V-165), inhibited the replication of HIV-1(III(B)) in MT-4 cells at a 50% effective concentration (EC(50)) of 8.9 microM, which is 14-fold below its cytotoxic concentration. V-165 was equally active against virus strains that were resistant toward inhibitors of viral entry or reverse transcriptase. In combination regimens in cell culture, V-165 acted subsynergistically with zidovudine or nelfinavir and synergistically with nevirapine. V-165 inhibited both reverse transcriptase and integrase activities in enzymatic assays at micromolar concentrations, but only a close correlation was found between the anti-HIV activity observed in cell culture and the inhibitory activity in the integrase strand transfer assays. Time-of-addition experiments indicated that V-165 interfered with the viral replication cycle at a time point coinciding with integration. Quantitative Alu-PCR corroborated that the anti-HIV activity of V-165 is based upon the inhibition of proviral DNA integration.
  
  
  CONCLUSIONS
  Based on their mode of action, which is different from that of clinically approved anti-HIV drugs, PDPs are good candidates for further development into new drugs and to be included in future combination regimens.
authors.affiliation: Rega Institute for Medical Research, KULeuven, Minderbroedersstraat 10, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Wim
authors.initials: W
authors.lastname: Pluymers
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Van Maele
authors.forename: Victor
authors.initials: V
authors.lastname: Tetz
authors.forename: Peter
authors.initials: P
authors.lastname: Cherepanov
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Myriam
authors.initials: M
authors.lastname: Witvrouw
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D002460:Cell Line; D005822:Genetic Vectors; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019428:HIV Integrase Inhibitors; D011743:Pyrimidines