Development of urea-bridged cyclic dominant negative pneumococcus competence-stimulating peptide analogs

Cyclization is a widely used approach to exert conformational restraint on linear peptide sequences. Herein, urea bridge chemistry was deployed to achieve side chain-to-side chain peptide cyclization on the <i>Streptococcus pneumoniae</i> CSP1-E1A peptide scaffold. To determine the effects of ring size and bridge position on the overall peptide conformation and find the ideal area within the CSP sequence for cyclization, we performed biological evaluation as well as secondary structure analysis on all the cyclic analogs. Biological evaluation results exhibited that even minor modifications to cyclic analogs for each of the cyclization positions could significantly alter the interaction between the peptide and its target receptor, ComD. Furthermore, structural analysis using circular dichroism (CD) and Trapped Ion Mobility Spectrometry (TIMS) emphasized the significance of incorporating the bridge position as a parameter to be modified, in addition to the traditional ring position and ring size parameters. Overall, our results showcase the importance of comprehensive conformational screening in fine-tuning the secondary structure of cyclic peptide analogs. This knowledge could be very useful for future studies aimed at optimizing peptide : protein interactions.