- Improving Selectivity, Proteolytic Stability, and Antitumor Activity of Hymenochirin-1B: A Novel Glycosylated Staple Strategy
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As a host defense peptide, hymenochirin-1B has attracted increasing attention for its strong cytotoxic activities. However, its poor selectivity and proteolytic stability remain major obstacles for clinical application. To solve these problems, we designed and synthesized a series of peptide analogues of hymenochirin-1B based on cationic residue substitution and stapling combined with a glycosylation strategy. Some analogues showed improvement not only in selectivity and proteolytic stability but also in antitumor activity. Among them, the glycosylated stapled peptide H-58 was identified as the most potential antitumor peptide. Flow cytometry and a competitive binding assay revealed that H-58 displayed significant antitumor selectivity. Confocal microscopy and nuclear staining with Hoechst dye demonstrated that H-58 entered the nucleus and caused DNA damage. In summary, the strategy of glycosylated stapled peptides is a promising approach for improving the antitumor selectivity, proteolytic stability, and antitumor activity of hymenochirin-1B, which can be used for other bioactive peptide modifications.
- Li, Yulei,Zhang, Yihan,Wu, Minghao,Chang, Qi,Hu, Honggang,Zhao, Xia
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- Site-Selective Chemoenzymatic Glycosylation of an HIV-1 Polypeptide Antigen with Two Distinct N-Glycans via an Orthogonal Protecting Group Strategy
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A convergent chemoenzymatic approach for sequential installation of different N-glycans in a polypeptide is described. The method includes introduction of distinguishably protected GlcNAc-Asn building blocks during automated solid phase peptide synthesis (SPPS), followed by orthogonal deprotection of the GlcNAc primers and site-selective sequential extension of the sugar chains through glycosynthase-catalyzed transglycosylation reactions. It was observed that the protecting groups on one neighboring GlcNAc moiety have an impact on the substrate activity of another GlcNAc acceptor toward some endoglycosynthases in transglycosylation. The usefulness of this synthetic strategy was exemplified by an efficient synthesis of the glycopeptide neutralizing epitope of broadly HIV-neutralizing antibody PG9. The method should be generally applicable for the synthesis of complex glycopeptides carrying multiple different N-glycans.
- Toonstra, Christian,Amin, Mohammed N.,Wang, Lai-Xi
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- Synthesis of PNGase-resistant N-glycopeptide containing an α-anomeric glycosidic linkage
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N-glycans in eukaryotic proteins are commonly attached to asparagine residues via β-N-glycosidic linkages, which are susceptible to glycosidases, such as PNGase. Here we report the preparation of α-N-glycosylated peptides based on the solid-phase peptide synthesis strategy using an α-N-GlcNAc-containing asparagine building block, and a transglycosylation reaction of oligosaccharide oxazoline promoted by endoglycosidases CCN180H. The resultant glycopeptide, bearing the complex-type α-N-sialyl undecasaccharide, exhibits resistance against PNGase F, which may be of potential use in studying the catabolism of N-glycans and glycoengineering those peptide-based therapeutics.
- Dao, Yuankun,Dong, Suwei,Dong, Weidong,Zhang, Jun
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- Synthesis of Asparagine Derivatives Harboring a Lewis X Type DC-SIGN Ligand and Evaluation of their Impact on Immunomodulation in Multiple Sclerosis
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The protein myelin oligodendrocyte glycoprotein (MOG) is a key component of myelin and an autoantigen in the disease multiple sclerosis (MS). Post-translational N-glycosylation of Asn31 of MOG seems to play a key role in modulating the immune response towards myelin. This is mediated by the interaction of Lewis-type glycan structures in the N-glycan of MOG with the DC-SIGN receptor on dendritic cells (DCs). Here, we report the synthesis of an unnatural Lewis X (LeX)-containing Fmoc-SPPS-compatible asparagine building block (SPPS=solid-phase peptide synthesis), as well as asparagine building blocks containing two LeX-derived oligosaccharides: LacNAc and Fucα1-3GlcNAc. These building blocks were used for the glycosylation of the immunodominant portion of MOG (MOG31-55) and analyzed with respect to their ability to bind to DC-SIGN in different biological setups, as well as their ability to inhibit the citrullination-induced aggregation of MOG31-55. Finally, a cytokine secretion assay was carried out on human monocyte-derived DCs, which showed the ability of the neoglycopeptide decorated with a single LeX to alter the balance of pro- and anti-inflammatory cytokines, inducing a tolerogenic response.
- Doelman, Ward,Marqvorsen, Mikkel H. S.,Chiodo, Fabrizio,Bruijns, Sven C. M.,van der Marel, Gijsbert A.,van Kooyk, Yvette,van Kasteren, Sander I.,Araman, Can
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p. 2742 - 2752
(2020/12/29)
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- Total Synthesis of Glycosylated Human Interferon-γ
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Interferon-γ(IFN-γ) is a glycoprotein that is responsible for orchestrating numerous critical immune induction and modulation processes and is used clinically for the treatment of a number of diseases. Herein, we describe the total chemical synthesis of homogeneously glycosylated variants of human IFN-γusing a tandem diselenide-selenoester ligation-deselenization strategy in the C- to N-terminal direction. The synthetic glycoproteins were successfully folded, and the structures and antiviral functions were assessed.
- Ashhurst, Anneliese S.,Dowman, Luke J.,Fairbanks, Antony J.,Kwan, Ann,Larance, Mark,Li, Henry Y.,Payne, Richard J.,Wang, Xiaoyi,Watson, Emma E.
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p. 6863 - 6867
(2020/09/15)
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- INHIBITION OF NGLY1 FOR THE TREATMENT OF CANCER
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In one aspect, the present disclosure provides GlcNAc-Asn analogs of the formula (I): wherein the variables are as defined herein. In another aspect, the present disclosure also provides pharmaceutical compositions and methods of using the compounds disclosed herein. Additionally, the present disclosure also provides methods of treating cancer comprising inhibiting NGLY1.
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- Native N-glycopeptide thioester synthesis through N→S acyl transfer
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Peptide thioesters are important tools for the total synthesis of proteins using native chemical ligation (NCL). Preparation of glycopeptide thioesters, that enable the assembly of homogeneously glycosylated proteins, is complicated by the perceived fragile nature of the sugar moiety. Herein, we demonstrate the compatibility of thioester formation via N→S acyl transfer with native N-glycopeptides and report observations that will aid in their preparation.
- Premdjee, Bhavesh,Adams, Anna L.,MacMillan, Derek
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p. 4973 - 4975
(2011/10/09)
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- Reaction of N-Fmoc aspartic anhydride with glycosylamines: a simple entry to N-glycosyl asparagines
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The reaction of N-Fmoc-aspartic anhydride with glycosyl amines in DMSO selectively leads to the formation of β-substituted products, thus providing a simple and efficient route to N-glycosyl asparagine derivatives, the building blocks for glycopeptide synthesis.
- Ibatullin, Farid M.,Selivanov, Stanislav I.
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experimental part
p. 6351 - 6354
(2010/02/27)
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- Amino acid fluoride for glycopeptide synthesis
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The formation of N-glycosidic linkage between N-acetylglucosamine (GlcNAc) and asparagine (Asn) was effected using aspartic acid γ-fluoride in combination with either glycosyl azide or silyl carbamate, by the action of Lindlar catalyst or Bu4NF. Further elongation of peptide chain was performed to give pentapeptide. This method was further applied into the synthesis of trisaccharidic asparagine, using p-methoxybenzyl assisted stereoselective β- mannosylation as the key transformation. (C) 2000 Elsevier Science Ltd.
- Ito, Yukishige,Gerz, Manfred,Nakahara, Yoshiaki
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p. 1039 - 1042
(2007/10/03)
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- Novel sequential solid-phase synthesis of N-linked glycopeptides from natural sources
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In the present report a practical and versatile procedure for the solid-phase synthesis of N-linked glycopeptides from natural sources has been demonstrated. The approach is based on the mild hydrazinolysis procedure to release N-linked oligosaccharides in their intact unreduced form from the natural glycoproteins, e.g. fetuin and ribonuclease B and subsequent formation of the corresponding glycosylamines. Treatment of the reducing sugars 1-7 with a saturated solution of ammonium hydrogen carbonate in either water or dimethyl sulfoxide (DMSO) gives in almost quantitative yields the glycosylamines 8-14. Coupling of the unprotected glycosylamines 8-14 to the side-chain-activated aspartic acid derivative Fmoc-Asp(ODhbt)-OBut 16 affords the N-glycosylated asparagine derivatives 17-23. Subsequent acetylation of the carbohydrate hydroxy groups and cleavage of the tert-Bu ester by trifluoroacetic acid (TFA) treatment yields the glycosylated N-linked building blocks 31-37. The building blocks 31-37 are then incorporated into the multiple-column peptide-synthesis protocol of the glycopeptide T-cell epitope analogues 40-46 of the mouse haemoglobin-derived decapeptide Hb (67-76), VITAFNEGLK. The decapeptide sequence VITAFNEGLK binds well to the MHC Class II Ek molecule and is non-immunogenic in CBA/J mice. Syntheses of several natural and unnatural glycosylations, e.g. N-acetylglucosamine, N,N′-diacetylchitobiose, glucose, maltotriose, maltoheptose and di- and triantennary complex oligosaccharides on the decapeptide Hb (67-76) affording the N-linked glycopeptides 40-46 are described. The N-linked glycopeptides 40-46 have been fully characterised by 1D- and 2D-1H and 13C NMR spectroscopy and by ES-MS.
- Meinjohanns, Ernst,Meldal, Morten,Paulsen, Hans,Dwek, Raymond A.,Bock, Klaus
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p. 549 - 560
(2007/10/03)
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- Synthesis of major histocompatibility complex class I binding glycopeptides
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Four Major Histocompatibility Complex (MHC) Class I binding glycopeptides and two peptide analogues, from a cytotoxic T-lymphocyte (CTL) epitope of Sendai Virus Nucleoprotein, have been prepared using solid-phase peptide synthesis employing the following glycosyl amino acid building blocks: FmocSer(Ac3-β-D-GlcNAc)OH 1, FmocSer(Ac3-α-D-GalN3)OPfp 2, FmocAsn(Ac3-β-D-GlcNAc)OH 3 and FmocAsn(ac3-β-D-GalNAc)OH 4.Previously, we examined the influence of glycosylation on peptide binding to the MHC Class I molecule and CTL recognition of these peptides.The synthesis and characterization of compounds 1-4 as well as the resulting glycopeptides is described.In addition, results of NMR investigations demonstrating that peptide K3, and glycopeptides K3-O-GlcNAc and K3-O-GalNAc, show two distinct conformations in solution as a result of cis-trans isomerization about a Tyr-Pro amide bond are reported.
- Arsequell, Gemma,Haurum, John S.,Elliott, Tim,Dwek, Raymond A.,Lellouch, Annemarie C.
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p. 1739 - 1746
(2007/10/02)
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