Life science
Medical & healthcare, Drug development

Decoding glycocode using synthetic glycans
Department of Chemistry, Graduate School of Science
Assistant Professor Yoshiyuki Manabe

https://researchmap.jp/researchmap_manabe

Professor Koichi Fukase

https://researchmap.jp/read0076573

Life science

Abstract
Glycans, the third life chain, are involved in many biologicalphenomena, including infection, cell adhesion, immune response,and cancer. On the other hand, the diversity and heterogeneity ofglycan structures make their functional analysis and regulation difficult. Thus, pharmaceutical applications of glycans have been limited. We aim to decode and utilize the glycan information (glycocode)
based on our technology of precise glycan synthesis (Fig. 1). We
hope that our project will lead to the creation of novel glycodrugs.
We have achieved a practical synthesis of N-glycans (Fig. 2),
which are representative post-translationally modified glycans, andhave been studying their functions using synthetic compounds.

believe that elucidation and regulation of the glycan functions enables to restore the homeostatic disturbances in various diseases,
including cancer, immunological disorders, and neurological disorders. Such unprecedented approach is expected to lead innovative glycodrug development.

▍ Background & Results
N-Glycans have diverse structures and exhibit various functions based on their structures. For example, sialic acids, which
are located at the non-reducing end, provide a recognition site to
many pathogens to be closely related to various infectious diseases. In addition, they also control immune responses through therecognition by their recognition lectins (Siglecs). We have beenworking on the chemical synthesis of N-glycans for analyzing theirfunctions at the molecular level. A key step in N-glycan synthesisis the construction of branched structure. We employed the convergent route; the non-reducing end fragments are glycosylated atthe 3- and 6-positions of branched mannose, respectively. These
key glycosylations involve difficulties because the large fragments
are linked at the sterically hindered positions. We have achieved
these glycosylation in high yields by using ether solvents effect,
which promoted the desired glycosylation by stabilizing the oxocarbenium ion intermediate. Furthermore, perfect stereoselectivityof these glycosylations was achieved by utilizing remote participation. These investigations realized practical synthesis of N-glycans.
Here, we analyzed the molecular basis of sialic acid recognition byneuraminidase, which has important role in influenza infection (Fig.
3). To investigate the difference in recognition of the non-reducing
terminal branches of N-glycans, we synthesized 1 and 2, in which
only one of the branches was labeled with deuterium. In addition,
to evaluate the effect of the branching number (= number of sialicacids) on neuraminidase recognition, a tetraantennary N-glycan3 was also synthesized. Analysis using these synthetic glycans
revealed that the neuraminidase preferentially recognizes the sialic
acid on the lower branch and that the number of branches has little
effect on substrate recognition by the neuraminidase.

Fig. 1

Fig. 2▍ Significance of the research and Future perspective
Glycans are closely related to various diseases. For example,
many diseases are caused by disturbances in homeostasis, andglycans play an important role in maintaining the homeostasis.
Therefore, glycans are widely used as diagnostic biomarkers. We

Fig. 3

P a t e n t
Tr e a t i s e

Shirakawa, A; Manabe, Y; Fukase, K et al. Chemical Synthesis of Sialyl N-Glycans and Analysis of Their Recognition by Neuraminidase. Angew. Chem. Int.
Ed. 2021, 60, 24686-24693, doi: 10.1002/anie.202111035

URL
K e y w o r d glycocode, carbohydrate synthesis, glycan, N-glycan, immunity