Enhancing cyclic peptide functionality with hydrophilic diamino acids for improved APC-Asef interaction inhibition

Cyclic peptides inherently possess advantages in inhibiting protein-protein interactions (PPIs). However, those constructed using traditional disulfide bonds are susceptible to cleavage by disulfide isomerase or reducing environments, leading to diminished biological activity. To address this challenge, our study employed novel hydrophilic diamino acids with enhanced electronegativity to construct cyclic peptides, effectively resolving issues related to stability and aqueous solubility, thereby overcoming the limitations associated with disulfide bond-based cyclic peptides. Furthermore, we applied this diamino acid strategy to the APC-Asef PPI peptide inhibitor MAI-516. Compared to cyclic peptides constructed using traditional disulfide bonds, those generated using the diamino acid strategy exhibited enhanced aqueous solubility, stability, and inhibitory activity. This study provides an application example for the modification of novel hydrophilic diamino acids in peptide cyclization and offers an effective strategy for the development of therapeutic agents for metastatic colorectal cancer.