3'-(1,2,3-Triazol-1-yl)-3'-deoxythymidine analogs as substrates for human and Ureaplasma parvum thymidine kinase for structure-activity investigations.
The pathogenic mycoplasma Ureaplasma parvum (Up) causes opportunistic infections and relies on salvage of nucleosides for DNA synthesis and Up thymidine kinase (UpTK) provides the necessary thymidine nucleotides. The anti-HIV compound 3 -azido-3'-deoxythymidine (AZT) is a good substrate for TK. Methods for a rapid and efficient synthesis of new 3'-alpha-[1,2,3]triazol-3'-deoxythymidine analogs from AZT under Huisgen conditions are described. Thirteen 3'-analogues were tested with human cytosolic thymidine kinase (hTK1) and UpTK. The new analogs showed higher efficiencies (K(m)/V(max) values) in all cases with UpTK than with hTK1. Still, hTK1 was preferentially inhibited by 9 out of 10 tested analogs. Structural models of UpTK and hTK1 were constructed and used to explain the kinetic results. Two different binding modes of the nucleosides within the active sites of both enzymes were suggested with one predominating in the bacterial enzyme and the other in hTK1. These results will aid future development of anti-mycoplasma nucleosides.
Lin
Jay
J
Department of Anatomy, Physiology and Biochemistry, Veterinary Medical Biochemistry, Swedish University Agricultural Sciences, Uppsala, Sweden.
Roy
Vincent
V
Wang
Liya
L
You
Li
L
Agrofoglio
Luigi A
LA
Deville-Bonne
Dominique
D
McBrayer
Tamara R
TR
Coats
Steven J
SJ
Schinazi
Raymond F
RF
Eriksson
Staffan
S
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000737:chemistry* / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014509:Ureaplasma / Q000187:drug effects / Q000201:enzymology; D015215:Zidovudine / Q000138:chemical synthesis / Q000737:chemistry
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D015215:Zidovudine; D013937:Thymidine Kinase; D013936:Thymidine