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Title: Design, synthesis and biological evaluation of novel anti-HCV nucleosides and nucleotides : from bench to the clinical trials
Author: Madela, Karolina
ISNI:       0000 0004 2734 2991
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2012
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The search for new anti-HCV therapeutics continues, as current standard of care based on pegINF and ribavirin is limited and can cause significant side effects. Several families of modified nucleoside are known to inhibit HCV RNA dependent RNA polymerase (RdRp). The 2’-C-!-methylguanosine (2’CMeG) has been identified as one of the most potent RdRp inhibitors (IC50 = 0.26 μM as NTP). Despite its very good activity at the triphosphate level its poor cell uptake and presumably poor phosphorylation lead to significant decrease in active in HCV replicon assays (EC50 = 3.5μM). The ProTide approach was applied to 2’-Cmethylguanosine in order to by-pass the first phosphorylation limiting step and enhance cellular uptake. Modified nucleoside phosphoramidates with improved efficacy and selectivity may become a future of HCV therapies. In the present work, the pronucleotide approach based on aryloxyphosphoramidate, phosphorodiamidate or oxazaphosphorine cyclic prodrugs has been applied to 2’-C-!-methylguanosine and related nucleoside analogues bearing modifications in C6-, C8- and C2- of the purine base. These modifications were mainly introduced to increase lipophilicity of 2’CMeG and consequently enhance cellular uptake and to deliver the 2’-C-methylguanosine 5’-monophosphate intracellularly. In general, most of the newly synthesised compounds exhibited excellent potency in HCV replicon assay. The most potent compounds were up to 1000-fold more active than the corresponding parent nucleoside. Base modification combined with the ProTide approach provide compounds that possess not only excellent antiviral activity but also good cell permeability. Extensive in vitro and in vivo studies lead to the selection of INX-08189 that has now progressed into human clinical trials for HCV, being currently in phase IIa clinical development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; RM Therapeutics. Pharmacology ; RS Pharmacy and materia medica