Selective targeting to macrophages of a new homodinucleotide active aginst human immunodeficiency virus and herpes simplex virus

Monocyte-derived macrophages (MDMs) play a central role in the pathogenesis of infection by human immunodeficiency virus (HIV) and represent the main reservoir of the virus in the body. In addition, MDMs can also be easily infected by various herpes viruses, including herpes simplex type I (HSV-1). As for HIV, macrophages can become a natural reservoir for latent HSV-1; moreover, herpes viruses are able to activate and increase HIV-replication. Hence therapeutic strategies able to inhibit replication of both viruses in macrophages are needed. 9-(2-Phosphonomethoxyethyl)adenine (PMEA) belongs to a new class of nucleotide analogs with strong and selective activity against several retroviruses, including HIV-1 and several herpes viruses, including HSV-1. PMEA is therefore of interest as a potential drug for the treatment of HIV infection and some of the opportunistic infections associated with AIDS.. However, the high anion charge of the phosphonate moiety of PMEA is held responsible for the rather low cellular uptake of the drug. To overcome this limitation and to increase the selective delivery of PMEA to macrophages, a compound consisting of two molecules of PMEA bound togheter (Bis-PMEA) was synthesized and encapsulated into autologous erythrocytes modified to increase their recognition and phagocytosis by human macrophages. Once inside macrophages, metabolic activation of the drug occurred. The addition of Bis-PMEA-loaded erythrocytes to human macrophages provided effective in vitro protection against HIV-1 and HSV-1 replication. Therefore Bis-PMEA acts as an efficient antiviral prodrug following selective targeting to macrophages by means of loaded erythrocytes