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

P. Franchetti, L. Rossi, L. Cappellacci, M. Pasqualini, M. Grifantini, E. Balestra, F. Forbici, C. F. Perno, S. Serafini, M. Magnani

Research output: Contribution to journalArticle

Abstract

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 pro-drug 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.

Original languageEnglish
Pages (from-to)151-159
Number of pages9
JournalAntiviral Chemistry and Chemotherapy
Volume12
Issue number3
Publication statusPublished - 2001

Fingerprint

Zidovudine
Adenine
HIV-1
Erythrocytes
Macrophages
Tenofovir
Viruses
Anti-HIV Agents
Prodrugs
Virus Diseases
Nucleosides
Half-Life
Permeability
Phosphates
HIV
(P(1)-thymidine-3'-azido-2',3'-dideoxyriboside-5')-P(2)-(9-2-(phosphonomethoxypropyl)adenine)
Enzymes
Pharmaceutical Preparations

Keywords

  • Azidothymidine (R)-PMPA
  • Erythrocytes
  • HIV
  • Macrophages

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

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.

In: Antiviral Chemistry and Chemotherapy, Vol. 12, No. 3, 2001, p. 151-159.

Research output: Contribution to journalArticle

Franchetti, P. ; Rossi, L. ; Cappellacci, L. ; Pasqualini, M. ; Grifantini, M. ; Balestra, E. ; Forbici, F. ; Perno, C. F. ; Serafini, S. ; Magnani, M. / 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. In: Antiviral Chemistry and Chemotherapy. 2001 ; Vol. 12, No. 3. pp. 151-159.
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AU - Rossi, L.

AU - Cappellacci, L.

AU - Pasqualini, M.

AU - Grifantini, M.

AU - Balestra, E.

AU - Forbici, F.

AU - Perno, C. F.

AU - Serafini, S.

AU - Magnani, M.

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