title: Erythrocyte-mediated delivery of a new homodinucleotide active against human immunodeficiency virus and herpes simplex virus.
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.
authors.affiliation: Institute of Biochemistry G. Fornaini, University of Urbino, 61029 Urbino, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rossi
authors.forename: S
authors.initials: S
authors.lastname: Serafini
authors.forename: L
authors.initials: L
authors.lastname: Cappellacci
authors.forename: E
authors.initials: E
authors.lastname: Balestra
authors.forename: G
authors.initials: G
authors.lastname: Brandi
authors.forename: G F
authors.initials: GF
authors.lastname: Schiavano
authors.forename: P
authors.initials: P
authors.lastname: Franchetti
authors.forename: M
authors.initials: M
authors.lastname: Grifantini
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: M
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000502:physiology*; D015497:HIV-1 / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates
chemical_list: D000998:Antiviral Agents; D002250:Carbon Radioisotopes; D063065:Organophosphonates; C430424:bis-9-(2-phosphonylmethoxyethyl)adenine; C053001:adefovir; D000225:Adenine