Synthesis and Structure-activity Relationship of Novel Guanidinium-containing Mitochondria-Targeting Peptoids

Abstract

The development of mitochondria-specific delivery methods is a prerequisite for studying mitochondria-related diseases and their treatment methods. Peptoid (i.e., oligo-N-substituted glycine) is a proteolysis-resistant peptidomimetic which is a promising scaffold in mitochondria targeting systems, along with peptide-based transporters. Considering the features of guanidinium ions, which are weakly hydrated compared to primary amines and can form salt bridges with phosphate groups in phospholipids, we designed a novel series of guanidinium-rich amphipathic peptoids with variations in hydrophobicity and net charges. We discovered that an overall increase in hydrophobicity did not improve mitochondrial localization while retaining high cell permeability. Moreover, a certain degree of positive charge was found to be critical for mitochondrial localization. As a continued effort to identify a selective mitochondrial transporter, we designed a novel cationic residue that contains a cyclic-guanidinie moiety. Peptoid monomer mimicking natural L-allo-enduracididine amino acid was synthesized (i.e., Nend(Cbz)2 monomer), and peptoids containing the Nend residue are being synthesized. In conclusion, our study provides a bioactive cargo delivery system for selective mitochondria-targeting via novel peptoids with sequence variation and monomeric composition.