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Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

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Journal of Biomedical Science

Summary

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-κB (NF-κB).

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Acknowledgements

The work was supported by grant no. 1M 6138896301 from the Centre for New Antivirals and Antineoplastics. It was performed as a part of research projects of the Institute of Experimental Medicine no. AV0 Z50390512 and the Institute of Organic Chemistry and Biochemistry no. Z40550506.

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Authors and Affiliations

  1. Institute of Experimental Medicine, Department of Immunopharmacology, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Vídeňská 1083, 142 20, Prague 4, Czech Republic

    Petr Potměšil, Eva Kmoníčková, Jana Křížková & Zdeněk Zídek

  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic

    Antonín Holý

  3. Institute of Pharmacology, Faculty of Medicine, Charles University, Karlovarská 48, 301 66, Pilsen, Czech Republic

    Eva Kmoníčková

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  1. Petr Potměšil
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Correspondence to Petr Potměšil.

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Potměšil, P., Holý, A., Kmoníčková, E. et al. Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3. J Biomed Sci 14, 59–66 (2007). https://doi.org/10.1007/s11373-006-9116-4

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  • DOI: https://doi.org/10.1007/s11373-006-9116-4

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