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

Wen Liu, Xing Wang, Rishi Pai, Jiahao Zhang, Christina Tran, Lei Li, Zhicheng Jin

Abstract readReview

In one paragraph

Review in ACS biomaterials science & engineering, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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7 authors.

Wen LiuDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.ORCID 0009-0001-9333-2981

Xing WangDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.ORCID 0000-0002-6080-4540

Rishi PaiDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.ORCID 0009-0003-7250-0813

Jiahao ZhangDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.

Christina TranDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.

Lei LiDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.ORCID 0000-0002-1146-0761

Zhicheng JinDepartment of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States.ORCID 0000-0001-6072-7533

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Amino AcidsFluorenesPeptidesSolid-Phase Synthesis TechniquesHumansHydrophobic and Hydrophilic InteractionsSolubilityWater9-fluorenylmethoxycarbonylAmino AcidsFluorenesN(alpha)-fluorenylmethyloxycarbonylamino acidsPeptidesWaterbiomaterialsFmoc chemistrynoncanonical amino acidsside-chain engineeringsolid-phase peptide synthesiswater solubility

Identifiers

PMID41891893

DOI10.1021/acsbiomaterials.5c02185

PMCPMC13080775

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