AZT and AZT-monophosphate Prodrugs Incorporating HIV-protease Substrate Fragment: Synthesis and Evaluation as Specific Drug Delivery Systems

• Published in: Antiviral chemistry & chemotherapy 2006, Vol.17 (4), p.193-213
• Main Authors: Liotard, Jean-François, Mehiri, Mohamed, Di Giorgio, Audrey, Boggetto, Nicole, Reboud-Ravaux, Michèle, Aubertin, Anne-Marie, Condom, Roger, Patino, Nadia
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiretroviral drugs; Antiviral activity; Antiviral agents; Biological and medical sciences; Cells, Cultured; Cytotoxicity; Dideoxynucleotides; Drug delivery; Drug Delivery Systems; Drug Evaluation; Drug Stability; Esters - chemical synthesis; High-performance liquid chromatography; HIV; HIV Infections - drug therapy; HIV Protease - chemistry; HIV Protease - drug effects; HIV-1 - drug effects; Human immunodeficiency virus; Human viral diseases; Humans; Hydrolysis; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Inhibitory Concentration 50; Medical sciences; Metabolites; Models, Biological; Nucleoside analogs; Peptides; Pharmacology. Drug treatments; Phosphoric Acids - chemical synthesis; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - therapeutic use; Protease Inhibitors - pharmacology; Proteinase; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Thymine Nucleotides - chemical synthesis; Thymine Nucleotides - therapeutic use; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Zidovudine; Zidovudine - analogs & derivatives; Zidovudine - chemical synthesis; Zidovudine - therapeutic use
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020601700404

With the view to deliver anti-HIV nucleoside and nucleoside-monophosphate (MP) analogues specifically into HIV-infected cells, we synthesized a series of ester and phosphoramidate peptide conjugates of zidovudine (AZT) and of AZT-MP, respectively, wherein the peptide sequences derive from a HIV-protease (PR) hydrolysable substrate. Their in vitro stability with respect to hydrolysis, anti-HIV activity and cytotoxicity, and ability to inhibit the HIV-PR activity were investigated. Concerning the ester AZT-peptide conjugates, their antiviral activity level in thymidine kinase-expressing (TK+) CEM-SS and MT-4 cells was in most cases closely correlated to their hydrolysis rate: the faster the hydrolysis, the closer the anti-HIV activity to that of AZT. None of them was a HIV-PR substrate, indicating that their antiviral activity was not related to their intracellular hydrolysis by this enzyme. None of them inhibited HIV in TK-deficient (TK−) CEM cells, demonstrating that they probably act as prodrugs of AZT. Most of the phosphoramidate peptide conjugates of AZT-MP were rapidly degraded in a physiological buffer into several metabolites including AZT. Their anti-HIV activity in TK+ CEM-SS and MT-4 cells was much lower than that of AZT, indicating that only low amounts of AZT or AZT-MP were released into cells during incubation. Antiviral activities measured on TK− CEM cells for some phosphoramidates suggest that low amounts of AZT-MP could be released intracellularly. However, this AZT-MP release was not initiated by a HIV-PR hydrolysis, as no evidence for peptide cleavage was obtained by HPLC analysis of one representative compound after incubation with HIV-PR.