Targeting nucleotide dimers containing antiviral nucleosides

L. Rossi, S. Serafini, P. Franchetti, L. Cappellacci, A. Fraternale, A. Casabianca, G. Brandi, F. Pierigé, C. F. Perno, E. Balestra, U. Benatti, E. Millo, M. Grifantini, M. Magnani

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Among the antiviral agents developed for the treatment of human viral infections, nucleoside analogs represent the largest group. However, much remains to do to improve their pharmacokinetic properties, to increase their efficacy, to reduce the selection of drug-resistent strains and to reduce their toxic side effects. Towards this end many nucleotide dimers have been synthesized in the last years in several laboratories. Such compounds have several advantages compared to the administration of nucleoside analogs as single drugs: 1) can act as prodrugs for a slow delivery of monomers in circulation; 2) can be encapsulated into autologous erythrocytes to perform as bioreactors converting a non diffusible dimer into a diffusible nucleoside analog to be released in circulation; 3) can be targeted to macrophages by proper drug targeting systems; 4) can overcome the limiting phosphorylating activities of several infectable cell types; 5) can have the advantage of a combination therapy with the administration of a single compound. In this review, dimers developed in our laboratory will be reported. In particular, the heterodinucleotide AZTpPMPA and the homodinucleotide Bis-PMEA are shown to be able to act as prodrugs when administered to mice releasing the single monomer in circulation. The homodinucleotide AZTp2AZT and the dimer AZTp2EMB once encapsulated in human erythrocytes are converted by erythrocyte enzymes into diffusible nucleosides and slowly released from the carrier cells. The dimers AZTp2AZT, AZTp2ACV, ACVpPMPA, AZTpPMPA and Bis-PMEA were targeted to macrophages where a very effective protection against virus replications was obtained. Thus, nucleotide dimers could be used as effective prodrugs for drug delivery in the treatment of viral infections improving the pharmacokinetic of single moieties and can be efficiently targeted to selected cell types with intracellular release of a phosphorylated (active) nucleoside.

Original languageEnglish
Pages (from-to)37-57
Number of pages21
JournalCurrent Medicinal Chemistry: Anti-Infective Agents
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 2005

Fingerprint

Nucleosides
Antiviral Agents
Nucleotides
Prodrugs
Erythrocytes
Virus Diseases
Pharmacokinetics
Macrophages
Pharmaceutical Preparations
Poisons
Bioreactors
Drug Delivery Systems
Virus Replication
Therapeutics
Enzymes
bis-9-(2-phosphonylmethoxyethyl)adenine
(P(1)-thymidine-3'-azido-2',3'-dideoxyriboside-5')-P(2)-(9-2-(phosphonomethoxypropyl)adenine)
azidothymidine homodinucleotide

Keywords

  • anti HIV-1 activity
  • anti HSV-1 activity
  • Erythrocytes
  • Heterodinucleotide
  • Homodinucleotide
  • Human macrophages
  • Murine AIDS
  • Pharmacokinetic properties

ASJC Scopus subject areas

  • Pharmacology
  • Infectious Diseases

Cite this

Rossi, L., Serafini, S., Franchetti, P., Cappellacci, L., Fraternale, A., Casabianca, A., ... Magnani, M. (2005). Targeting nucleotide dimers containing antiviral nucleosides. Current Medicinal Chemistry: Anti-Infective Agents, 4(1), 37-57. https://doi.org/10.2174/1568012052931214

Targeting nucleotide dimers containing antiviral nucleosides. / Rossi, L.; Serafini, S.; Franchetti, P.; Cappellacci, L.; Fraternale, A.; Casabianca, A.; Brandi, G.; Pierigé, F.; Perno, C. F.; Balestra, E.; Benatti, U.; Millo, E.; Grifantini, M.; Magnani, M.

In: Current Medicinal Chemistry: Anti-Infective Agents, Vol. 4, No. 1, 01.2005, p. 37-57.

Research output: Contribution to journalArticle

Rossi, L, Serafini, S, Franchetti, P, Cappellacci, L, Fraternale, A, Casabianca, A, Brandi, G, Pierigé, F, Perno, CF, Balestra, E, Benatti, U, Millo, E, Grifantini, M & Magnani, M 2005, 'Targeting nucleotide dimers containing antiviral nucleosides', Current Medicinal Chemistry: Anti-Infective Agents, vol. 4, no. 1, pp. 37-57. https://doi.org/10.2174/1568012052931214
Rossi L, Serafini S, Franchetti P, Cappellacci L, Fraternale A, Casabianca A et al. Targeting nucleotide dimers containing antiviral nucleosides. Current Medicinal Chemistry: Anti-Infective Agents. 2005 Jan;4(1):37-57. https://doi.org/10.2174/1568012052931214
Rossi, L. ; Serafini, S. ; Franchetti, P. ; Cappellacci, L. ; Fraternale, A. ; Casabianca, A. ; Brandi, G. ; Pierigé, F. ; Perno, C. F. ; Balestra, E. ; Benatti, U. ; Millo, E. ; Grifantini, M. ; Magnani, M. / Targeting nucleotide dimers containing antiviral nucleosides. In: Current Medicinal Chemistry: Anti-Infective Agents. 2005 ; Vol. 4, No. 1. pp. 37-57.
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