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).