title: 4,6-dibenzamidopyrazolo[3,4-d]pyrimidine is a highly selective inhibitor of cytomegalovirus adsorption to cells.
abstract: The heterocycle, 4,6-dibenzamidopyrazolo[3,4-d]pyrimidine (DBAPP), inhibited cytopathology induced by human, mouse, and vervet monkey cytomegaloviruses (CMV) in vitro at 0.2 to 0.5 microM, but did not inhibit cell replication at less than or equal to 30 microM. Herpes simplex viruses were unaffected by the inhibitor. The antiviral agent ganciclovir was effective against these CMVs at 3-10 microM in parallel assays. DBAPP and ganciclovir were synergistic inhibitors when used in combination. The heterocycle was only active if applied to cells before virus replication, indicating that it inhibited virus adsorption. Cells pre-treated 1 h with 30 microM DBAPP, then extensively rinsed, were resistant to infection by mouse CMV even 3 days after removal of the inhibitor. Human and monkey CMVs were able to infect cells and replicate within 24 h of drug removal. When virus and DBAPP were combined together then dialyzed to remove the compound, mouse CMV infectivity was decreased 1.7 logs, whereas human CMV and monkey CMV infectivity titers were relatively unaffected. Treatment of mice with DBAPP twice a day for 7 days starting 6 h after mouse CMV inoculation caused a moderate increase in number of survivors at 30 mg/kg. Cell to cell spread of the virus may account for poor efficacy of the compound when added after virus infection. DBAPP may serve as a tool to explore aspects of CMV adsorption or to characterize the cellular component of the CMV receptor.
authors.affiliation: Nucleic Acid Research Institute, Costa Mesa, CA 92626.
authors.forename: D F
authors.initials: DF
authors.lastname: Smee
authors.forename: M L
authors.initials: ML
authors.lastname: Bartlett
authors.forename: H A
authors.initials: HA
authors.lastname: Alaghamandan
authors.forename: M M
authors.initials: MM
authors.lastname: Jones
authors.forename: G R
authors.initials: GR
authors.lastname: Revankar
authors.forename: R K
authors.initials: RK
authors.lastname: Robins
mesh_terms: D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002521:Cercopithecus; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003864:Depression, Chemical; D004357:Drug Synergism; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011720:Pyrazoles; D011743:Pyrimidines; C063938:4,6-dibenzamidopyrazole(3,4-d)pyrimidine; D015774:Ganciclovir