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Inhibition of HIV-1 replication in macrophages by red blood cell-mediated delivery of a heterodinucleotide of azidothymidine and 9-(R)-2-(phosphono methoxypropyl)adenine.
Franchetti, P; Rossi, L; Cappellacci, L; Pasqualini, M; Grifantini, M; Balestra, E; Forbici, F; Perno, C F; Serafini, S; Magnani, M.
Afiliação
  • Franchetti P; Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy. frapa@camserv.unicam.it
Antivir Chem Chemother ; 12(3): 151-9, 2001 May.
Article em En | MEDLINE | ID: mdl-12959323
Monocyte-derived macrophages (M/M) are considered important in vivo reservoirs for different kinds of viruses, including HIV. Hence, therapeutic strategies are urgently needed to protect these cells from virus infection or to control viral replication. In this paper, we report the synthesis, target delivery and in vitro efficacy of a new heterodinucleotide (AZTpPMPA), able to inhibit HIV-1 production in human macrophages. AZTpPMPA consists of two established anti-HIV drugs [zidovudine (AZT) and tenofovir (PMPA)] chemically coupled together by a phosphate bridge. This drug is not able to prevent p24 production when administered for 18 h to M/M experimentally infected with HIV-1 Bal (inhibition 27%), but can almost completely suppress virus production when given encapsulated into autologous erythrocytes (inhibition of p24 production 97%). AZTpPMPA is slowly converted to PMPA, AZT monophosphate and AZT (36 h half-life at 37 degrees C) by cell-resident enzymes. Thus AZTpPMPA should be considered a new prodrug of AZT and PMPA that is able to provide stechiometric amounts of both nucleoside analogues to macrophage cells and to overcome the low phosphorylating activity of M/M for AZT and the modest permeability of PMPA.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenina / Zidovudina / HIV-1 / Sistemas de Liberação de Medicamentos / Fármacos Anti-HIV / Eritrócitos / Macrófagos Limite: Humans Idioma: En Ano de publicação: 2001 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adenina / Zidovudina / HIV-1 / Sistemas de Liberação de Medicamentos / Fármacos Anti-HIV / Eritrócitos / Macrófagos Limite: Humans Idioma: En Ano de publicação: 2001 Tipo de documento: Article