Inhibition constants ( s) were used as an estimate of the ability of various nucleoside analogues to be recognized as substrates by the deoxythymidine kinases (dTKs) of a 5-methoxymethyldeoxyuridine-resistant (MMdU) mutant of herpes simplex virus type 1 (HSV-1) and its parent wild-type (wt). It was found that the s for the 5-position analogues MMdU, []-5-(2-bromovinyl)deoxyuridine, bromodeoxyuridine and iododeoxyuridine were increased approximately three-to fivefold, suggesting that they were poorer substrates for the MMdU dTK than for the wt dTK. With the 2′ analogues arabinosylthymine and 2′ fluoro 5-methylarabinosyluracil, however, the s were increased to a much greater extent, 80- and 240-fold, respectively. These findings suggest that the resistance of the mutant MMdU to these analogues may be due to a mutation(s) in the viral dTK that directly affects binding at the 2′ recognition site and indirectly at the 5, while still allowing substantial activity with the natural substrate deoxythymidine.


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