title: Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3.
abstract: Acyclic nucleoside phosphonates are potent antiviral agents effective against replication of DNA viruses and retroviruses including human immunodeficiency virus (HIV). In addition to their antimetabolic mode of antiviral action, acyclic nucleoside phosphonates also possess immunomodulatory properties. We have shown recently that a number of them stimulate secretion of cytokines including chemokines RANTES/CCL5 ("regulated upon activation, normal T cell expressed and secreted") and MIP-1 alpha/CCL3 (macrophage inflammatory protein-1 alpha) that may inhibit entry of HIV in cells. In present experiments we analyzed effects of acyclic nucleoside phosphonates on gene expression of other members of the beta family of chemokines, monocyte chemotactic proteins (MCPs), which have also been implicated in the control of HIV infection. The following compounds differing at the type of heterocyclic base, i.e. adenine (A), or 2,6-diaminopurine (DAP), at the 6-amino group of the base, and at the N ( 9 )-side chain represented by 9-[2-(phosphonomethoxy)ethyl] (PME) and 9-[2-(phosphonomethoxy)propyl] (PMP) moieties were included in the study: (1) (R)-PMPA, ie. tenofovir, (2) N ( 6 )-cyclopropyl-(R)-PMPDAP, (3) N ( 6 )-cyclopentyl-(R)-PMPDAP, (4) N ( 6 )-dimethylaminoethyl-(R)-PMPDAP, (5) N ( 6 )-cyclopentyl-PMEDAP, (6) N ( 6 )-isobutyl-PMEDAP, (7) N ( 6 ) -cyclohexylmetyl-PMEDAP, and (8) N ( 6 ) -cyclooctyl-PMEDAP. These compounds are able to activate production of MCP-1 and MCP-3, and none of them influences gene expression of MCP-2, and MCP-5. Enhancement of monocyte chemotactic protein expression was found to be mediated by transcriptional factor nuclear factor-kappaB (NF-kappaB).
authors.affiliation: Institute of Experimental Medicine, Department of Immunopharmacology, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Prague 4, Czech Republic. potmesil@biomed.cas.cz
authors.forename: Petr
authors.initials: P
authors.lastname: Potmesil
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Eva
authors.initials: E
authors.lastname: Kmonícková
authors.forename: Jana
authors.initials: J
authors.lastname: Krízková
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Zídek
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D043422:Carboxypeptidases A / Q000096:biosynthesis* / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D006678:HIV / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D009705:Nucleosides; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse