Chemoenzymatic Synthesis of the Immunoglobulin Domain of Tim‐3 Carrying a Complex‐Type N‐Glycan by Using a One‐pot Ligation

Asahina, Yuya; Kamitori, Shigehiro; Takao, Toshifumi; Nishi, Nozomu; Hojo, Hironobu

doi:10.1002/anie.201303073

Cited by 65 publications

(40 citation statements)

References 56 publications

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“…Moreover, coupling of the O-acyl isopeptide as a building block by the segment condensation method [21][22][23][24][25] or chemical ligation [26][27][28][29][30][31][32][33] yielded the long-chain polypeptide as the O-acyl form, which enabled synthesis of hydrophobic, and thus synthetically challenging, proteins. For example, amylin, 24) transmembrane domain peptide, 26) saposin-C, 27,28) Tim-3 immunoglobulin domain, 29) S100A4 calcium-binding protein, 31) and interleukin-2 32) were successfully synthesized in this manner. In addition, numerous applications of the O-acyl isopeptide as a precursor of the target peptide, in a similar manner to those of Aβ and amylin (see below), have been reported.…”

Section: O-acyl Isopeptide Methodsmentioning

confidence: 99%

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Sohma

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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The aggregation of peptides/proteins is intimately related to a number of human diseases. More than 20 have been identified which aggregate into fibrils containing extensive β-sheet structures, and species generated in the aggregation processes (i.e., oligomers and fibrils) contribute to disease development. Amyloid-β peptide (designated Aβ), related to Alzheimer's disease (AD), is the representative example. The intensive aggregation property of Aβ also leads to difficulty in its synthesis. To improve the synthetic problem, we developed an O-acyl isopeptide of Aβ1-42, in which the N-acyl linkage (amide bond) of Ser 26 was replaced with an O-acyl linkage (ester bond) at the side chain. The O-acyl isopeptide demonstrated markedly higher watersolubility than that of Aβ1-42, while it quickly converted to intact monomer Aβ1-42 via an O-to-N acyl rearrangement under physiological conditions. Inhibition of the pathogenic aggregation of Aβ1-42 might be a therapeutic strategy for curing AD. We succeeded in the rational design and identification of a small molecule aggregation inhibitor based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]. Moreover, the inhibition of Aβ aggregation was achieved via oxygenation (i.e., incorporation of oxygen atoms to Aβ) using an artificial catalyst. We identified a selective, cell-compatible photo-oxygenation catalyst of Aβ, a flavin catalyst attached to an Aβ-binding peptide, which markedly decreased the aggregation potency and neurotoxicity of Aβ.

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Section: O-acyl Isopeptide Methodsmentioning

confidence: 99%

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Sohma

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…[13] To apply the method, we first condensed the two Cterminal segments 2 and 3 using the Ag + -free thioester method. We previously developed as equential ligation method for three segments by using the thioester method, taking advantage of the reactivity difference between the aryl and alkyl thioesters.…”

Section: Angewandte Chemiementioning

confidence: 99%

Chemical Synthesis of O‐Glycosylated Human Interleukin‐2 by the Reverse Polarity Protection Strategy

et al. 2015

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The chemical synthesis of human interleukin-2 (IL-2) ,h aving ac ore 1s ugar,b yaligation method is reported. Although IL-2 is aglobular glycoprotein, its C-terminal region, in particular (99-133), is extremely insoluble when synthesized by solid-phase method. To overcome this problem, the sidechain carboxylic acid of the Glu residues was protected by ap icolyl ester,t hus reversing its polarity from negative to positive.This reverse polarity protection significantly increased the isoelectric point of the peptide segment and made it positive under acidic conditions and facilitated the purification. An efficient method to prepare the prolyl peptide thioester required for the synthesis of the (28-65) segment was also developed. These efforts resulted in the total synthesis of the glycosylated IL-2 having full biological activity.

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“…Starting from the resin having the NAC moiety, the peptide synthesis was carried out by the Fmoc method using a microwave peptide synthesizer, except for the lysine residues, which were manually introduced using Fmoc-Lys(iNoc)-OH by the diisopropylcarbodiimide (DIC)/1-hydroxybenzotriazole (HOBt) method in 1-methyl-2-pyrrolidinone (NMP). [24] At the Thr 3 glycosylation site, the unit Downloaded by [University of Newcastle, Australia] at 16:28 09 January 2015 residue. As expected from the results of Figure 1, the 2 h treatment with the TFA cocktail removed all of the protecting groups including the O-protecting groups of the carbohydrate moiety (Fig.…”

Section: Application For the Synthesis Of Peptide Thioester Il-2 (1-27)mentioning

confidence: 99%

“…Fmoc-Gly-(Et)Cys(Trt)-OH, [33] Fmoc-Lys(iNoc)-OH, [24] and 4-nitrophenyl 4-pyridylmethyl carbonate [24,34] (iNoc-ONp) were prepared according to previous reports. The specific rotation values were determined using a SEPA-300 polarimeter (Horiba, Kyoto).…”

Section: Experimental Section Generalmentioning

confidence: 99%

“…Along this line, we recently established the synthetic route of the complex-type carbohydrate lacking the reducing end GlcNAc. [23][24][25] In addition, we designed the GlcNAc-Asn unit carrying the substituted benzyl protecting group, which can yield an Nacetylglucosaminylated peptide by one-step deprotection with TFA after the Fmoc-SPPS. Using this method, we successfully synthesized the active domain of emmprin .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Fmoc-Thr Unit Carrying Core 1O-Linked Sugar With Acid-SensitiveO-Protecting Group and Its Application to the Synthesis of Glycosylated Peptide Thioester

Asahina

Fujimoto

Suzuki

et al. 2014

Journal of Carbohydrate Chemistry

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Y. Asahina et al.We newly designed and synthesized a 9-fluorenylmethoxycarbonyl (Fmoc)-threonine unit carrying the core 1 O-glycan, which is protected by the 4-methylbenzyl (MBn) group. This protection tactic enabled not only efficient assembly of glycoamino acid derivatives but also one-step deprotection by trifluoroacetic acid (TFA) after the Fmocsolid-phase peptide synthesis (SPPS). The usefulness of this unit was demonstrated by the Fmoc-SPPS of peptide thioester using the N-alkylcysteine (NAC)-assisted thioesterification method. The human interleukin-2 (1-27) sequence was assembled on the NAC resin and the obtained resin was treated with TFA containing cation scavengers to achieve one-step deprotection. The crude peptide was then thioesterified by reacting with an arylthiol to successfully obtain the desired peptide thioester carrying the core 1 O-glycan.

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Chemoenzymatic Synthesis of the Immunoglobulin Domain of Tim‐3 Carrying a Complex‐Type N‐Glycan by Using a One‐pot Ligation

Cited by 65 publications

References 56 publications

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Medicinal Chemistry Focusing on Aggregation of Amyloid-β

Chemical Synthesis of O‐Glycosylated Human Interleukin‐2 by the Reverse Polarity Protection Strategy

Synthesis of Fmoc-Thr Unit Carrying Core 1O-Linked Sugar With Acid-SensitiveO-Protecting Group and Its Application to the Synthesis of Glycosylated Peptide Thioester

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