Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction

Blocking
the interaction of MTDH/SND1 complex is an attractive
strategy for cancer therapeutics. In this work, we designed and obtained
a novel class of potent stabilized peptide inhibitors derived from
MTDH sequence to disrupt MTDH/SND1 interaction. Through structure-based
optimization and biological evaluation, stabilized peptides were obtained
with tight binding affinity, improved cell penetration, and antitumor
effects in the triple-negative breast cancer (TNBC) cells without
nonspecific toxicity. To date, our study was the first report to demonstrate
that stabilized peptides truncated from MTDH could serve as promising
candidates to disrupt the MTDH/SND1 interaction for potential breast
cancer treatment.