Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase

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.