Comparative study of purine and pyrimidine nucleoside analogues acting on the thymidylate kinases of Mycobacterium tuberculosis and of humans.

Sylvie Pochet (1) , Laurence Dugué (1) , Gilles Labesse (2) , Muriel Delepierre (3) , Hélène Munier-Lehmann (4)

1 Chimie Organique
2 CBS - Centre de Biochimie Structurale [Montpellier]
3 Résonance Magnétique Nucléaire des Biomolécules
4 CSM - Chimie Structurale des Macromolécules

Thymidine monophosphate kinase (TMPK) from Mycobacterium tuberculosis (TMPKmt) is an attractive target for the design of specific inhibitors. This fact is the result of its key role in the thymidine pathway and of unique structural features in the active site observed by X-ray crystallography, especially in comparison to its human counterpart (TMPKh). Different 5-modified thymidine derivatives, as well as purine and pyrimidine analogues or C-nucleosides were tested on TMPKmt and TMPKh, and the results were rationalized by docking studies. 5-Halogenated 2'-deoxyuridines are the best inhibitors of TMPKmt found and present the highest selectivity indexes in favor of TMPKmt.

Domains: Life Sciences [q-bio]; Biochemistry, Molecular Biology

Sylvie Pochet, Laurence Dugué, Gilles Labesse, Muriel Delepierre, Hélène Munier-Lehmann. Comparative study of purine and pyrimidine nucleoside analogues acting on the thymidylate kinases of Mycobacterium tuberculosis and of humans.. ChemBioChem, 2003, 4 (8), pp.742-7. ⟨10.1002/cbic.200300608⟩. ⟨pasteur-00165348⟩