Comparative Study of Purine and Pyrimidine Nucleoside Analogues Acting on the Thymidylate Kinases of <i>Mycobacterium tuberculosis</i> and of Humans

Pochet, Sylvie; Dugué, Laurence; Labesse, Gilles; Delepierre, Muriel; Munier‐Lehmann, Hélène

doi:10.1002/cbic.200300608

Cited by 53 publications

(62 citation statements)

References 31 publications

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“…Removal of the methyl group (dUMP) drastically affects the affinity (50-fold decrease) and the reaction rate (3-fold decrease). The 5-halogenated deoxyuridines counterparts are competitive inhibitors of TMPKmt with affinities quite similar to their corresponding nucleoside monophosphates [28]. 5-Cl-dU and 5-Br-dU are remarkably specific for TMPKmt versus TMPKh.…”

Section: -Base Modificationsmentioning

confidence: 94%

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Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Calenbergh¹,

Pochet²,

Munier‐Lehmann³

2012

CTMC

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Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases and preclude DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. TMPKmt, which is essential to DNA replication, was selected as a promising target for inhibitor design. This review will describe how stepwise modifications of the enzyme's substrate, guided by the feedback of the enzyme assays as well as crystallographic information, proved a valuable approach to produce potent TMPKmt inhibitors, some of which were also capable to inhibit bacterial growth. Perhaps more importantly, some of the reported thymidine analogues also represent valuable tools to better understand the structure and the mechanism of this intriguing enzyme.

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Section: -Base Modificationsmentioning

confidence: 94%

“…Base-modified nucleosides (i.e. non-phosphorylated) were also explored: purine and pyrimidine nucleosides and C-nucleosides [28]…”

Section: -Base Moiety Modificationsmentioning

confidence: 99%

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Calenbergh¹,

Pochet²,

Munier‐Lehmann³

2012

CTMC

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“…His-tagged Vacc-TMPK and human TMPK were synthesized and purified to homogeneity as previously described (20,41). The purified proteins were equilibrated by dialysis against 50 mM Tris⅐HCl (pH 7.5) buffer containing 20 mM NaCl, 1 mM DTT, and 50% glycerol.…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of poxvirus thymidylate kinase: An unexpected dimerization has implications for antiviral therapy

Caillat

Topalis

Agrofoglio

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.BVdU ͉ dihalovinyl-dU ͉ dimerization mode ͉ TMP kinase ͉ vaccinia virus

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“…TMPKmt and TMPKh production and purification have been described elsewhere. [7,14] TMPK activity was determined using the coupled spectrophotometric assay according to Blondin et al [30] at l = 334 nm in an Eppendorf ECOM 6122 spectrophotometer. The reaction medium (0.5 mL final volume) contained 50 mm Tris-HCl pH 7.4, 50 mm KCl, 2 mm MgCl 2 , 0.2 mm NADH, 1 mm phosphoenol pyruvate, and two units each of lactate dehydrogenase, pyruvate kinase, and nucleoside diphosphate kinase.…”

Section: Enzymatic Assaysmentioning

confidence: 99%

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

et al. 2008

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In the search for novel inhibitors of the enzyme thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt), an attractive target for novel antituberculosis agents, we report herein the discovery of the first acyclic nucleoside analogues that potently and selectively inhibit TMPKmt. The most potent compounds in this series are (Z)‐butenylthymines carrying a naphtholactam or naphthosultam moiety at position 4, which display Ki values of 0.42 and 0.27 μM, respectively. Docking studies followed by molecular dynamics simulations performed to rationalize the interaction of this new family of inhibitors with the target enzyme revealed a key interaction between the distal substituent and Arg 95 in the target enzyme. The fact that these inhibitors are more easily synthesizable than previously identified TMPKmt inhibitors, together with their potency against the target enzyme, makes them attractive lead compounds for further optimization.

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Comparative Study of Purine and Pyrimidine Nucleoside Analogues Acting on the Thymidylate Kinases of Mycobacterium tuberculosis and of Humans

Cited by 53 publications

References 31 publications

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Drug Design and Identification of Potent Leads Against Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Crystal structure of poxvirus thymidylate kinase: An unexpected dimerization has implications for antiviral therapy

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

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