Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions

Rong，Yongheng1; Wang，Xingyun2; Mao，Weian1; Yuan，Fang1; Chen，Min1; Wang，Shengjun3; Wang，Peng George2; Wu，Zhigang4; He，Yunjiao2; Kong，Yun1

2022

10.1021/acsinfecdis.2c00383

ACS Infectious Diseases   Impact Factor & Quartile

2373-8227

2373-8227

Harnessing highly conserved peptides derived from the receptor binding domain (RBD) of spike (S) protein to construct peptide-based inhibitors is one of the most effective strategies to fight against the ever-mutating coronavirus SARS-CoV-2. But how the O-glycosylation affects their inhibition abilities has not been intensively explored. Herein, an intrinsic O-glycosylated peptide P320-334 derived from RBD was screened and homogeneous O-linked glycopeptides containing Tn (GalNAcα1-O-Ser/Thr), T (Galβ1-3GalNAcα1-O-Ser/Thr), sialyl-Tn (sTn, Siaα2-6GalNAcα1-O-Ser/Thr), and sialyl-T (sT, Siaα2-3Galβ1-3GalNAcα1-O-Ser/Thr) structures were first synthesized via chemoenzymatic strategies. Compared with the unglycosylated peptide, the binding of sT-P320-334 to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P320-334 was significantly increased up to 150-410%. Thus, our results suggest the sialic acid residue on the terminal of short O-glycan structures might strengthen the inhibition capacities of these peptide-based inhibitors, which might provide novel optimization directions for the inhibitor design.

chemoenzymatic synthesis O-glycosylation modification peptide-based inhibitor SARS-CoV-2 spike protein

SCI

English

Corresponding

Shandong Province Key Research and Develop Program["2019 GSF 107048","2020CXGC010601"] ; National Natural Science Foundation of China["31500648","31971213"] ; Guangdong Basic, Applied Basic Research Foundation[2019A1515010647] ; Open Projects Fund of Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University[2019CCG08] ; Shenzhen Science and Technology Program[KQTD20200909113758004] ; Hebei Provincial Department of Human Resources and Social Security Grants["C201812","E2018100010"] ; Foundation of Hebei Educational Committee[QN2019217] ; Natural Science Foundation of Hebei Province[H2021208001]

Pharmacology & Pharmacy ; Infectious Diseases

Chemistry, Medicinal ; Infectious Diseases

WOS:000859282900001

AMER CHEMICAL SOC

2-s2.0-85138766314

Scopus

1.National Glycoengineering Research Center,Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology,State Key Laboratory of Microbial Technology,Shandong University,Qingdao,266237,China
2.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
3.School of Health and Life Sciences,University of Health and Rehabilitation Sciences,Qingdao,266071,China
4.College of Food and Biology,Hebei University of Science and Technology,Shijiazhuang,050018,China

Rong，Yongheng,Wang，Xingyun,Mao，Weian,et al. Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions[J]. ACS Infectious Diseases,2022,8(10).

Rong，Yongheng.,Wang，Xingyun.,Mao，Weian.,Yuan，Fang.,Chen，Min.,...&Kong，Yun.(2022).Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions.ACS Infectious Diseases,8(10).

Rong，Yongheng,et al."Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions".ACS Infectious Diseases 8.10(2022).