Imikhiqizo

I-Beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) iyisivimbeli esithile esinamandla segciwane le-hepatitis C (HCV) RNA synthesis kumaseli e-Huh-7 replicon.Ukuze uvimbele i-HCV NS5B RNA polymerase, i-PSI-6130 kufanele ibe ne-phosphorylated kufomu le-5'-triphosphate.I-phosphorylation ye-PSI-6130 kanye nokuvinjelwa kwe-HCV NS5B kuye kwaphenywa.I-phosphorylation ye-PSI-6130 nge-recombinant human 2'-deoxycytidine kinase (dCK) kanye ne-uridine-cytidine kinase 1 (UCK-1) ikalwe ngokusebenzisa ukusabela kwe-spectrophotometric okuhlanganisiwe.I-PSI-6130 iboniswe njenge-substrate ye-dCK ehlanzekile, ene-Km engu-81 microM kanye ne-kcat engu-0.007 s-1, kodwa yayingeyona i-substrate ye-UCK-1.I-PSI-6130 monophosphate (PSI-6130-MP) ifakwe kahle i-phosphorylated ku-diphosphate futhi kamuva yaba ku-triphosphate nge-recombinant UMP-CMP kinase yomuntu kanye ne-nucleoside diphosphate kinase, ngokulandelana.Ukuvinjelwa kohlobo lwasendle kanye nama-muted (S282T) HCV NS5B RNA polymerases kwacwaningwa.I-steady-state inhibition constant (Ki) ye-PSI-61 30 triphosphate (PSI-6130-TP) ene-enzayimu yohlobo lwasendle yayingu-4.3 microM.Imiphumela efanayo yatholwa nge-2'-C-methyladenosine triphosphate (Ki=1.5 microM) kanye ne-2'-C-methylcytidine triphosphate (Ki=1.6 microM).I-NS5B enokuguqulwa kwe-S282T, okwaziwa ngokunikeza ukumelana ne-2'-C-methyladenosine, yavinjwa i-PSI-6130-TP ngendlela ephumelelayo njengohlobo lwasendle.Ukufakwa kwe-PSI-6130-MP ku-RNA eyenziwe nge-NS5B RNA polymerase ehlanzekile kuholele ekunqanyulweni kweketango.