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Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
Author(s) -
Nurbo Johanna,
Roos Annette K.,
Muthas Daniel,
Wahlström Erik,
Ericsson Daniel J.,
Lundstedt Torbjörn,
Unge Torsten,
Karlén Anders
Publication year - 2007
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.906
Subject(s) - ribonucleotide reductase , peptide , chemistry , ribonucleotide , biochemistry , combinatorial chemistry , nucleotide , protein subunit , gene
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. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.