title: Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase.
abstract: Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that Trp5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain, as compared to Trp5.
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Nurbo
authors.forename: Annette K
authors.initials: AK
authors.lastname: Roos
authors.forename: Daniel
authors.initials: D
authors.lastname: Muthas
authors.forename: Erik
authors.initials: E
authors.lastname: Wahlström
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ericsson
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Lundstedt
authors.forename: Torsten
authors.initials: T
authors.lastname: Unge
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003001:Cloning, Molecular; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D021281:Quantitative Structure-Activity Relationship; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D013237:Stereoisomerism
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D012264:Ribonucleotide Reductases