Synthesis, Characterization and Erythrocyte Encapsulation of an Azidothymidine Homodinucleotide
A new nucleoside analogue, di(thymidine-3′-azido-2′,3′-dideoxy-D-riboside)-5′-5′-p1-p2-pyrophosphate (AZTp2AZT), was designed and synthesized to overcome some limitations of conventional antiretroviral chemotherapy based upon nucleoside analogues (AZT, ddC, ddI). Indeed, the triphosphorylated form of these nucleoside analogues is able to inhibit the infectivity and replication of Human Immunodeficiency Virus (HIV-1), but the main problems in the use of these drugs concern their limited phosphorylation in some cells (e.g., macrophages) and their cytotoxic side effects. AZTp2AZT was encapsulated in human erythrocytes according to a conservative procedure of hypotonic shock-isotonic resealing and reannealing and showed a remarkable stability and a slow conversion to 5′-monophosphate (AZT-MP) and to AZT. This azidothymidine homodinucleotide seems to have chemical and biochemical properties enabling its profitable utilization in the erythrocyte-encapsulated form.
KeywordsHuman Immunodeficiency Virus Human Immunodeficiency Virus Type Human Erythrocyte Nucleoside Analogue Anhydrous Pyridine
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- 1.Benatti, U., Giovine, M., Damonte, G., Gasparini, A., Scarfi, S., De Flora, A., Fraternale, A., Rossi, L. and Magnani, M. Azidothymidine homodinucleotide-loaded erythrocytes as bioreactors for slow delivery of the antiretroviral drug azidothymidine. Biochem. Biophys. Res. Commun. 220, 20–25, 1996.PubMedCrossRefGoogle Scholar
- 2.Beutler E; Red Cells Metabolism. A manual of Biochemical methods. Grune&Stratton, Orlando, 1984.Google Scholar
- 3.De Clercq, E. Basic approaches to anti-retroviral treatment. J. AIDS 4, 207–218, 1991.Google Scholar
- 5.Gasparini, A., Giovine, M., Damonte, G., Tonetti, M., Grandi, T., Mazzei, M., Balbi, A., Silvestro, L., Benatti, U. and De Flora, A. A novel dimeric fluoropyrimidine molecule behaves as a remote precursor of 5-fluoro-2′-deoxyuridine in human erythrocytes. Biochem. Pharmacol. 48, 1121–1128, 1994.PubMedCrossRefGoogle Scholar
- 11.Magnani, M., Casabianca, A., Fraternale, A., Brandi, G., Gessani, S., Williams, R., Giovine, M., Damonte, G., De Flora, A. and Benatti, U. Synthesis and targeted delivery of an azidothymidine homodinucleotide conferring protection to macrophages against retroviral infection. Proc. Natl. Acad. Sci. USA 93, 4403–4408, 1996.PubMedCrossRefGoogle Scholar
- 12.Perno, CF., Yarchoan, R., Cooney, D.A., Hartman, N.R., Gartner, S., Popovic, M., Hao, Z., Gerrard, T.L., Wilson, Y.A., Johns, D.G. and Broder, S. J. Inhibition of human immunodeficiency virus (HIV-1/HTLV-II-IBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2′,3′-dideoxynucleosides. J. Exp. Med. 168, 1111–1125, 1988.PubMedCrossRefGoogle Scholar
- 14.Yarchoan, R., Mitsuya, H., Myers, C.E. and Broder, S. Clinical pharmacology of 3′-azido-2′,3′-dide-oxythymidine (zidovudine) and related dideoxynucleosides. N. Engl. J. Med. 321, 726–738 1983.Google Scholar