tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Xingyun Wang[SUP] 2 [/SUP], Weian Mao[SUP] 1 [/SUP], Fang Yuan[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Shengjun Wang[SUP] 3 [/SUP], Peng George Wang[SUP] 2 [/SUP], Zhigang Wu[SUP] 4 [/SUP], Yunjiao He[SUP] 2 [/SUP], Yun Kong[SUP] 1 [/SUP]
Affiliations
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[SUB]320-334[/SUB] 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[SUB]320-334[/SUB] to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P[SUB]320-334[/SUB] 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.
. 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[SUP] 1 [/SUP], Xingyun Wang[SUP] 2 [/SUP], Weian Mao[SUP] 1 [/SUP], Fang Yuan[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Shengjun Wang[SUP] 3 [/SUP], Peng George Wang[SUP] 2 [/SUP], Zhigang Wu[SUP] 4 [/SUP], Yunjiao He[SUP] 2 [/SUP], Yun Kong[SUP] 1 [/SUP]
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[SUB]320-334[/SUB] 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[SUB]320-334[/SUB] to hACE2 was enhanced to 133% and the inhibition capacity against RBD-hACE2 binding of sTn- and sT-P[SUB]320-334[/SUB] 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.