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

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ACS Infect Dis


. 2022 Sep 12.
doi: 10.1021/acsinfecdis.2c00383. Online ahead of print.
Chemoenzymatic Synthesis of SARS-CoV-2 Homogeneous O-Linked Glycopeptides for Exploring Their Inhibition Functions


Yongheng Rong ¹ , Xingyun Wang ² , Weian Mao ¹ , Fang Yuan ¹ , Min Chen ¹ , Shengjun Wang ³ , Peng George Wang ² , Zhigang Wu ⁴ , Yunjiao He ² , Yun Kong ¹



Affiliations

• PMID: 36095241
• DOI: 10.1021/acsinfecdis.2c00383

Abstract

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 P_320-334 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-P_320-334 to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P_320-334 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.

Keywords: O-glycosylation modification; SARS-CoV-2; chemoenzymatic synthesis; peptide-based inhibitor; spike protein.