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

Abstract

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.

Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

“…The disruption of the MTDH-SND1 interaction was reported to be able to decrease the proliferation of MDA-MB-231 tumor cells. , We further evaluated the effects of L5 and C26-A6 on MDA-MB-231 cells using the CCK8 assay (Figure C and D). The cells were incubated with the two compounds at five different concentrations for 72 h, respectively.…”

“…c Data from ref . d Data from ref . The cellular antiproliferation IC 50 values of C26-A2 and C26-A6 were not reported, except that C26-A2 reduced the tumorshpere number by 60% and tumorshpere size by 30% at 200 μM concentration in a tumorshpere assay, while C26-A6 reduced the tumorshpere number and size by 75% and 50%, respectively, at the same concentration in the same assay from ref .…”

“…22 Soon after, Chen et al designed two stabilized peptides (MS2D-cyc4 and MS2D-cyc6) as MTDH-SND1 modulators through terminal aspartic acid stabilized strategy. 23 Meanwhile, Shen et al first identified a class of small molecule inhibitors (C26-A2 and C26-A6) through screening a singleton small chemical library consisting of ∼50,000 compounds. 24,25 As peptide inhibitors might usually suffer from issues like poor membrane permeability, intracellular instability, and poor bioavailability, 26,27 and the two reported small molecules lack cellular potency, in this work, by targeting this challenging protein−protein interaction interface, we proposed a molecular dynamics (MD) simulation-driven approach to efficiently and effectively identify novel small molecule inhibitors from over one billion compounds of the ZINC15 28 database.…”

Discovery and Design of Novel Cyclic Peptides as Specific Inhibitors Targeting CCN2 and Disrupting CCN2/EGFR Interaction for Kidney Fibrosis Treatment

“…Cyclic peptides often exhibit superior biological activity compared to their linear counterparts due to their conformational rigidity and resistance to proteolytic degradation. , Additionally, the larger surface area of cyclic peptides leads to higher affinity and selectivity for protein targets . Biologically active cyclic peptides usually consist of amino acids (typically ≤10 aa) linked together to form a macrocyclic ring structure. − Therefore, in this study, cyclic peptide OK2 or OK3 was synthesized by linking linear peptide K2 or K3 through head-to-tail cyclization, where an amide bond is formed between the amino and carboxy termini of each end (Figure A).…”

“…Cyclic peptides often exhibit superior biological activity compared to their linear counterparts due to their conformational rigidity and resistance to proteolytic degradation. 33,34 Additionally, the larger surface area of cyclic peptides leads to higher affinity and selectivity for protein targets. 35 Biologically active cyclic peptides usually consist of amino acids (typically ≤10 aa) linked together to form a macrocyclic ring structure.…”