title: Novel pseudopeptides incorporating a benzodiazepine-based turn mimetic--targeting Mycobacterium tuberculosis ribonucleotide reductase.
abstract: 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.
authors: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors: Johanna
authors: J
authors: Nurbo
authors: Daniel J
authors: DJ
authors: Ericsson
authors: Ulrika
authors: U
authors: Rosenström
authors: Daniel
authors: D
authors: Muthas
authors: Anna M
authors: AM
authors: Jansson
authors: Gunnar
authors: G
authors: Lindeberg
authors: Torsten
authors: T
authors: Unge
authors: Anders
authors: A
authors: Karlén
mesh_terms: D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D057786:Peptidomimetics; D001569:Benzodiazepines; D012264:Ribonucleotide Reductases