Design and evaluation of 5'-modified nucleoside analogs as prodrugs for an E. coli purine nucleoside phosphorylase mutant |
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Authors: | Parker William B Allan Paula W Ealick Steve E Sorscher Eric J Hassan Abdalla E A Silamkoti A V Fowler Anita T Waud William R Secrist John A |
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Institution: | Southern Research Institute, 2000 Ninth Ave., South, Birmingham, AL 35205, USA. parker@sri.org |
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Abstract: | Our studies have led to the identification of an E. coli PNP mutant (M64V) that is able to cleave numerous 5'-modified nucleoside analogs with much greater efficiency than the wild-type enzyme. The biological activity of the three best substrates of this mutant (9-6-deoxy-alpha-L-talofuranosyl]-6-methylpurine (methyl(talo)-MeP-R), 9-6-deoxy-alpha-L-talofuranosyl]-2-F-adenine, and 9-alpha-L-lyxofuranosyl]-2-F-adenine) were evaluated so that we can optimally utilize these compounds. Our results indicated that the mechanism of toxicity of methyl(talo)-MeP-R to mice was due to its cleavage to MeP by a bacterial enzyme, and that the toxicity of the two F-Ade analogs was due to their cleavage to F-Ade by mammalian methylthioadenosine phosphorylase. |
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