Approaches related to the synthesis of Fmoc-Ser/Thr[GalNAc(Ac)₃-α-D]-OH

Abstract

Protein O-glycosylation, particularly mucin-type glycosylation, plays important biological roles. However, the limited access to homogeneously glycosylated protein isoforms (glycoforms) has impeded the establishment of correlations between diverse glycan structures and protein properties, restricting therapeutic and diagnostic applications. Chemical synthesis of glycopeptides utilizing properly protected glycoamino acids as building blocks has emerged as a valuable approach to address the gap in glycoform acquisition. This review focuses on past efforts for the chemical synthesis of two fundamental glycoamino acid building blocks, Fmoc-Ser[GalNAc(Ac)₃-α-D]-OH and Fmoc-Thr[GalNAc(Ac)₃-α-D]-OH, by categorizing various methods based on glycosylation donors. The emphasis is on stereoselectivity, synthetic route length, and overall yield, with the goal of inspiring and guiding future research to further improve their synthetic efficiency and promote advancements in protein glycosylation studies and applications.

Graphical abstract

Keywords:

• Chemical synthesis
• glycoamino acids
• glycosylation donors
• stereoselectivity
• synthesis route

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

The authors thank the CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-026), the National Key R & D Program of China (Grant No. 2018YFE0111400), the NIH Research Project Grant Program (Grant No. R01 EB025892), the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, and the Biomedical High Performance Computing Platform, Chinese Academy of Medical Sciences and Peking Union Medical College, and the Xiaogan 3D Scientific Computing Center, for funding and support