Enhancing Peptide Hydrophilicity of SPPS-Derived Peptides Using Fmoc Noncanonical Amino Acids: A Review

Poor peptide solubility in water remains a major challenge in both peptide synthesis and downstream biomedical applications. Recent advances in 9-fluorenylmethoxycarbonyl (Fmoc) noncanonical Amino acids (ncAAs) enable rational side-chain design to enhance peptide hydrophilicity derived from solid-phase peptide synthesis (SPPS). This review discusses four major classes of ncAAs, cationic, anionic, polar nonionic, and zwitterionic, each improving water solubility through mechanisms such as charge introduction, charge balancing, and strong hydration. Together, these advances demonstrate how ncAAs can be strategically integrated through side-chain engineering in SPPS to produce more water-soluble peptides. Challenges, including side-chain stability and steric hindrance, as well as the need for efficient postassembly conjugation strategies, highlight the need for continued molecular and synthetic innovation, creating opportunities to integrate Fmoc-ncAAs into synthetic peptides for next-generation soluble peptidic biomaterials with broad biomedical impact.