Erythrocyte-mediated delivery of a new homodinucleotide active against human immunodeficiency virus and herpes simplex virus

Luigia Rossi, Sonja Serafini, Loredana Cappellacci, Emanuela Balestra, Giorgio Brandi, Giuditta F. Schiavano, Palmarisa Franchetti, Mario Grifantini, Carlo Federico Perno, Mauro Magnani

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Abstract

Monocyte-derived macrophages (MDMs) play a central role in the pathogenesis of infection by human immunodeficiency virus (HIV-1) and represent one of the main reservoirs of the virus in the body. In addition, MDMs can easily be infected by various herpes viruses, including herpes simplex virus type 1 (HSV-1). We have synthesized a new antiviral agent (Bis-PMEA) that consists of two 9-(2-phosphonylmethoxyethyl)adenine (PMEA) molecules bound by a phosphate bridge. This nucleotide analogue, like the parent compound PMEA, has strong and selective activity against HIV-1 and HSV-1. A drug-targeting system previously developed in our laboratory was used for the selective delivery of these drugs to macrophages. Bis-PMEA and PMEA were encapsulated into autologous erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. Loaded erythrocytes were modified to increase their recognition and phagocytosis by human macrophages. By administering Bis-PMEA-loaded erythrocytes to macrophages, 47% of Bis-PMEA and 28% of PMEA was still present 10 days after phagocytosis; in contrast, only 12% of PMEA was found in macrophages receiving PMEA-loaded erythrocytes. Bis-PMEA-loaded erythrocytes were then added to macrophages infected with HIV-1 and HSV-1 and their antiviral activity evaluated. Remarkable protection was obtained against HIV-1 and HSV-1 infection (95 and 85%, respectively). Therefore, Bis-PMEA acts as an efficient antiviral prodrug that, following selective targeting to macrophages by means of loaded erythrocytes, can protect a refractory cell compartment.

Original languageEnglish
Pages (from-to)819-827
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume47
Issue number6
Publication statusPublished - 2001

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ASJC Scopus subject areas

  • Pharmacology
  • Microbiology

Cite this

Rossi, L., Serafini, S., Cappellacci, L., Balestra, E., Brandi, G., Schiavano, G. F., Franchetti, P., Grifantini, M., Perno, C. F., & Magnani, M. (2001). Erythrocyte-mediated delivery of a new homodinucleotide active against human immunodeficiency virus and herpes simplex virus. Journal of Antimicrobial Chemotherapy, 47(6), 819-827.