Discovery of the First Highly Potent and Selective Peptide Inhibitor Targeting Microtubule-MAP7 Interaction via Structure-Based Design for Suppressing Colorectal Cancer Cell Proliferation.

Microtubules are core cytoskeletal components for cellular activities. Their interaction with microtubule-associated protein 7 (MAP7) is crucial for cell proliferation, cellular component transport, and morphological regulation. The conserved microtubule surface region binds tightly to MAP7's microtubule-binding domain (MTBD). Its function relates closely to tumorigenesis and progression. Using structure-based drug design, we first designed peptides 1-3, peptide inhibitors targeting microtubule-MAP7 interaction. These peptides disrupt microtubule-MAP7 interaction by specifically binding to microtubules. After multiple optimizations, peptide-3's binding affinity to microtubules reaches 0.12 μM. Further studies show that it effectively inhibits the proliferation, migration, and invasion of colorectal cancer cells (HCT116 and SW480) and enhances cell damage. Animal experiments confirm its potent in vivo antitumor activity with no obvious toxicity. In summary, peptide-3 specifically disrupts microtubule-MAP7 interaction, acting as a promising lead compound for inhibiting colon cancer cell proliferation.