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
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...
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| Veröffentlicht in: | Antiviral chemistry & chemotherapy 2001-06, Vol.12 (3), p.151-159 |
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| creator | Franchetti, P Rossi, L Cappellacci, L Pasqualini, M Grifantini, M Balestra, E Forbici, F Perno, C-F Serafini, S Magnani, M |
| description | 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°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. |
| doi_str_mv | 10.1177/095632020101200302 |
| format | Article |
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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°C) by cell-resident enzymes. 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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°C) by cell-resident enzymes. 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| ispartof | Antiviral chemistry & chemotherapy, 2001-06, Vol.12 (3), p.151-159 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenine Adenine - analogs & derivatives Adenine - chemistry Adenine - metabolism Adenine - pharmacology Anti-HIV Agents - chemistry Anti-HIV Agents - metabolism Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiretroviral drugs Antiviral agents Biological and medical sciences Cell Adhesion Chromatography, High Pressure Liquid Dideoxynucleotides Drug Delivery Systems Drug Stability Erythrocytes Erythrocytes - metabolism HIV HIV-1 - drug effects Human immunodeficiency virus Human immunodeficiency virus 1 Humans In Vitro Techniques Macrophages Macrophages - drug effects Macrophages - virology Medical sciences Monocytes Nucleoside analogs Permeability Pharmacology. Drug treatments Replication Tenofovir Virus Replication - drug effects Zidovudine Zidovudine - analogs & derivatives Zidovudine - chemistry Zidovudine - metabolism Zidovudine - pharmacology |
| title | 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 |
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