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Bourdin, Claire
Languages: English
Types: Doctoral thesis
Subjects: QR180, RM, QR355
Hepatitis C virus is an infectious disease affecting millions of people worldwide and causing chronic liver disease. The current standard of care is not only long but causes numerous side effects. Due to incomplete virological response and poor tolerability, only 50% of the patients are cured, with variability by genotype. Despite the\ud development of non-enzymatic viral protein inhibitors, new therapies target mainly enzymes responsible for viral replication or translation. Being commonly used for\ud antiviral and anticancer therapy, nucleosides analogues have played an important role as anti-HCV agents.\ud Despite their potency and selectivity, nucleoside analogues appear to be poor substrates for metabolic enzymes. In particular, the first essential phosphorylation step is often rate-limiting thus, resulting in poor bioactivation to the active triphosphate form. Hence, monophosphate prodrug strategies have been applied to efficiently deliver\ud intracellularly the key monophosphate derivatives. Such strategies have been successfully used for anti-HCV therapy and the phosphoramidate ProTide INX-08189, discovered in our lab, is one such example.\ud Aiming at developing back-up molecules of INX-08189, we report in the present work, the synthetic strategies to obtain several modified β-2’-C-methyl-6-O-methyl guanosine\ud and other modified β-2’-C-methyl purine nucleoside analogues. The phosphoramidate ProTide approach and the phosphorodiamidate approach were applied to these modified\ud nucleosides. In-vitro, and sometimes in-vivo evaluation against HCV replication is reported, and the mechanism of bioactivation to their corresponding monophosphate\ud species is discussed. Enzymatic experiments using carboxypeptidase Y and Huh-7 cell lysates were carried out to investigate the release of the monophosphate forms. We also investigated the hydrolysis of the 6-O-methyl group at the nucleoside level with adenosine deaminase enzyme, and at the monophosphate level using molecular docking\ud in adenosine deaminase like protein-1. Eventually, the intracellular putative mechanism of activation of the ProTides was studied using molecular modeling with cathepsin A enzyme and human Hint-1 phosphoramidase.
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