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Research article2010Peer reviewedOpen access

3 '-(1,2,3-Triazol-1-yl)-3 '-deoxythymidine analogs as substrates for human and Ureaplasma parvum thymidine kinase for structure-activity investigations

Lin, Jay; Roy, V; Wang, Liya; Agrofoglio, LA; Deville-Bonne, D; McBrayer, TR; Coats, SJ; Schinazi, SF; You, L; Eriksson, Staffan

Abstract

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 30-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. (C) 2010 Elsevier Ltd. All rights reserved.

Keywords

Thymidine kinase; Mycoplasma; Nucleoside analogs; Microwave; Click-chemistry; Structure function-relationship; AZT; Ureaplasma parvum; Huisgen reaction

Published in

Bioorganic and Medicinal Chemistry
2010, volume: 18, number: 9, pages: 3261-3269
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

SLU Authors

UKÄ Subject classification

Animal and Dairy Science
Veterinary Science

Publication identifier

  • DOI: https://doi.org/10.1016/j.bmc.2010.03.023

Permanent link to this page (URI)

https://res.slu.se/id/publ/48193