Synthesis and in Vitro Biological Evaluation of Mannose-Containing Prodrugs Derived from Clinically Used HIV-Protease Inhibitors with Improved Transepithelial Transport
| Autor: | ‡ and Anne-Marie Aubertin, Pierre Vierling, Dominique Roche, Jacques Greiner |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cell Membrane Permeability
viruses medicine.medical_treatment Biomedical Engineering Pharmaceutical Science Mannose Bioengineering Pharmacology chemistry.chemical_compound immune system diseases In vivo Indinavir medicine Humans HIV Protease Inhibitor Prodrugs Protease Molecular Structure Chemistry Organic Chemistry HIV virus diseases Epithelial Cells HIV Protease Inhibitors biochemical phenomena metabolism and nutrition Prodrug Nelfinavir Biochemistry Caco-2 Cells Saquinavir Biotechnology medicine.drug |
| Zdroj: | Bioconjugate Chemistry. 17:1568-1581 |
| ISSN: | 1520-4812 1043-1802 |
| Popis: | In an approach to improve the pharmacological properties, safety and pharmacokinetic profiles, and their penetration into HIV reservoirs or sanctuaries, and consequently, the therapeutic potential of the current protease inhibitors (PIs) used in clinics, we investigated the synthesis of various mannose-substituted saquinavir, nelfinavir, and indinavir prodrugs, their in vitro stability with respect to hydrolysis, anti-HIV activity, cytotoxicity, and permeation through a monolayer of Caco-2 cells used as a model of the intestinal barrier. Mannose-derived conjugates were prepared in two steps, in good yields, by condensing an acid derivative of a protected mannose with the PIs, followed by deprotection of the sugar protecting group. With respect to hydrolysis, these PI prodrugs are chemically stable with half-life times in the 50-60 h range that are compatible with an in vivo utilization aimed at improving the absorption/penetration or accumulation of the prodrug in specific cells/tissues and liberation of the active free drug inside HIV-infected cells. These stabilities correlate closely with the low in vitro anti-HIV activity measured for those prodrugs wherein the coupling of mannose to the PIs was performed through the peptidomimetic PI's hydroxyl. Importantly, mannose conjugation to the PIs was further found to improve the absorptive transepithelial transport of saquinavir and indinavir but not of nelfinavir across Caco-2 cell monolayers, by contrast to glucose conjugation which had the opposite effect. The mannose-linked prodrugs of saquinavir and indinavir display therefore a most promising therapeutic potential provided that bioavailability, penetration into the HIV infected macrophages, and HIV-reservoirs of these PIs are improved. |
| Databáze: | OpenAIRE |
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