Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic--targeting Mycobacterium tuberculosis ribonucleotide reductase.

Johanna Nurbo, Daniel J Ericsson, Ulrika Rosenström, Daniel Muthas, Anna M Jansson, Gunnar Lindeberg, Torsten Unge, Anders Karlén

Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.

Bioorganic & medicinal chemistry 2013 Apr 1

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Peptides mimicking the C-terminus of the small subunit (R2) of Mycobacterium tuberculosis ribonucleotide reductase (RNR) can compete for binding to the large subunit (R1) and thus inhibit RNR activity. Moreover, it has been suggested that the binding of the R2 C-terminus is very similar in M. tuberculosis and Salmonella typhimurium. Based on modeling studies of a crystal structure of the holocomplex of the S. typhimurium enzyme, a benzodiazepine-based turn mimetic was identified and a set of novel compounds incorporating the benzodiazepine scaffold was synthesized. The compounds were evaluated in a competitive fluorescence polarization assay and in an RNR activity assay. These studies revealed that the compounds incorporating the benzodiazepine scaffold have the ability to compete for the M. tuberculosis R2 binding site with low-micromolar affinity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Citation

Johanna Nurbo, Daniel J Ericsson, Ulrika Rosenström, Daniel Muthas, Anna M Jansson, Gunnar Lindeberg, Torsten Unge, Anders Karlén. Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic--targeting Mycobacterium tuberculosis ribonucleotide reductase. Bioorganic & medicinal chemistry. 2013 Apr 1;21(7):1992-2000