title: Purine P1 receptor-dependent immunostimulatory effects of antiviral acyclic analogues of adenine and 2,6-diaminopurine.
abstract: Acyclic nucleoside phosphonates are widely recognised antivirals. The oral prodrugs of prototype compounds, e.g., 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir), and 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] were approved by FDA for treatment of hepatitis B (Hepsera), and acquired immunodeficiency syndrome (AIDS) (Viread), respectively. A number of acyclic nucleoside phosphonates possess immunostimulatory activity. The present experiments demonstrate that activation of cytokine and chemokine secretion is mediated by adenosine receptors. Included in the study were 9-(R)-[2-(phosphonomethoxy)propyl]adenine [tenofovir], N(6)-cyclopentyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, N(6)-cyclopropyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, and N(6)-isobutyl-9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine. All of them activate secretion of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), "regulated on activation of normal T cell expressed and secreted" (RANTES/CCL5), and macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) in murine macrophages. With exception of MIP-1alpha, the effects were inhibited by antagonists of adenosine A(1), A(2B), and A(3) receptors (not by adenosine A(2A) receptor antagonist). The adenosine A(1) receptor antagonist inhibited TNF-alpha, IL-10, and RANTES, adenosine A(2B) receptor antagonist inhibited TNF-alpha and RANTES, and adenosine A(3) receptor antagonist inhibited IL-10 and RANTES. The suppression is due to decreased transcription of cytokine mRNA. It may be suggested that acyclic nucleoside phosphonates are nonspecific ligands for purine P(1) receptors.
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague. kmonickova@biomed.cas.cz
authors.forename: Eva
authors.initials: E
authors.lastname: Kmonícková
authors.forename: Petr
authors.initials: P
authors.lastname: Potmesil
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Zídek
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005415:Flavins / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D063065:Organophosphonates / Q000276:immunology / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D004095:Dihydropyridines; D005415:Flavins; D008070:Lipopolysaccharides; C107728:MRS 1191; D019402:Macrophage Inflammatory Proteins; D063065:Organophosphonates; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C081320:8-(3-chlorostyryl)caffeine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D002110:Caffeine; D015075:2-Aminopurine; C008173:isoalloxazine; C007300:2,6-diaminopurine; D013806:Theophylline; D000225:Adenine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine