Nucleoside kinases, rate-limiting step of nucleoside analogues activation

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چکیده

Nucleoside analogues have proven to be a highly successful class of anti-cancer and anti-viral drugs. The therapeutic efficacy of nucleoside analogues is dependent of their intracellular phosphorylation. Two cellular nucleoside kinases, deoxycytidine kinase (dCK) and UMP-CMP kinase (CMK) are critical for phosphorylation of cytidine analogues. These kinases provide two first steps of activation of highly effective anti-cancer and anti-viral drugs, such as 1-β-Darabinofuranosylcytosine (araC, aracytidine), 2’,2’difluorodeoxycytidine (dFdC, gemcitabine), β-D-2’3’dideoxycytidine (ddC). Both kinases phosphorylate unnatural L-nucleosides (e.g., β-L-2’3’-dideoxy-3’thiacytidine, LSSdC, 3-TC or lamividune). Kinetic constants of araC, dFdC and 3TC phosphorylation by recombinant dCK and UMP-CMPK have been published. The comparison of phosphorylation properties of new nucleoside analogues with those of known drugs provides the rational basis for selection of analogues of better therapeutic potential. To characterize the phosphorylation properties of new nucleoside analogues, NovoCIB has developed human recombinant dCK and human recombinant CMK nucleoside phosphorylation assays. As shown in Table 1, CMK assay must be performed with monophosphate forms of nucleoside analogues and requires preliminary phosphorylation of nucleoside analogues and their purification. To circumvent this time-consuming step, NovoCIB has developed a coupled dCK-CMK nucleoside phosphorylation assay that delivers in one step the critical information on both dCK and CMK substrate properties of nucleoside analogue.

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تاریخ انتشار 2010