Modular Design and Self‐assembly of pH‐Responsive Multidomain Peptides Incorporating Non‐natural Ionic Amino Acids

• Published in: Chemistry : a European journal 2024-12, Vol.30 (67), p.e202403085-n/a
• Main Authors: Asokan‐Sheeja, Haritha, Das, Debdatta, Nguyen, Jenny N., Nguyen, Na, Van Khanh Pham, Tran, Nguyen, Kytai T., Dong, He
• Format: Article
• Language: English
• Subjects: Amino acids; Amino Acids - chemistry; Antimicrobial; Antimicrobial activity; Antimicrobial agents; Biomedical materials; Dismantling; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Modular design; Non-natural amino acids; Peptide self-assembly; Peptides; Peptides - chemistry; pH effects; pH-responsive; Self-assembly; Static Electricity; Structure-Activity Relationship
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202403085

Stimuli‐responsive peptides, particularly pH‐responsive variants, hold significant promise in biomedical and technological applications by leveraging the broad pH spectrum inherent to biological environments. However, the limited number of natural pH‐responsive amino acids within biologically relevant pH ranges presents challenges for designing rational pH‐responsive peptide assemblies. In our study, we introduce a novel approach by incorporating a library of non‐natural amino acids featuring chemically diverse tertiary amine side chains. Hydrophobic and ionic properties of these non‐natural amino acids facilitate their incorporation into the assembly domain when uncharged, and electrostatic repulsion promotes disassembly under lower pH conditions. Furthermore, we observed a direct relationship between the number of substitutions and the hydrophobicity of these amino acids, influencing their pH‐responsive properties and enabling rational design based on desired transitional pH ranges. The structure‐activity relationship of these pH‐responsive peptides was evaluated by assessing their antimicrobial properties, as their antimicrobial activity is triggered by the disassembly of peptides to release active monomers. This approach not only enhances the specificity and controllability of pH responsiveness but also broadens the scope of peptide materials in biomedical and technological applications. A new class of acid‐responsive peptide assembly incorporating non‐natural ionic amino acids is reported. The transition pH of these assemblies is dictated by the hydrophobic microenvironment around the ionic residues and highly tunable in the weakly acidic range. These materials demonstrate great potential for the development of acid‐activatable antimicrobial therapy.