Traceless chemical ligations from O-acyl serine sites

Khatib, Mirna El; Elagawany, Mohamed; Jabeen, Farukh; Todadze, Ekaterina; Bol’shakov, Oleg; Oliferenko, Alexander A.; Khelashvili, Levan; El‐Feky, Said A.; Asiri, Abdullah M.; Katritzky, Alan R.

doi:10.1039/c2ob07050b

Cited by 21 publications

(24 citation statements)

References 31 publications

(26 reference statements)

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“…[9] This key discovery laid the intellectual framework for the development of ligation-deselenization chemistry at unnatural selenol-derived amino acids, [10] including in our laboratory at phenylalanine (Phe). It should be noted that other strategies for ligation at Ser junctions have recently been explored, including the use of thiol auxiliaries linked via the Ser side-chain, [12] ligation at Ser through the rearrangement of O-acyl isopeptides [13] or direct ligation with activated salicylaldehyde (SAL) esters. [10b,11] Invoking as imilar mechanism to that proposed for the chemoselective deselenization of Sec, [9] we presumed that this intriguing byproduct resulted from reaction of ab enzylic radical with dissolved oxygen in the reaction media.…”

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confidence: 99%

Oxidative Deselenization of Selenocysteine: Applications for Programmed Ligation at Serine

et al. 2015

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Despite the unique chemical properties of selenocysteine (Sec), ligation at Sec is an under-utilized methodology for protein synthesis. We describe herein an unprecedented protocol for the conversion of Sec to serine (Ser) in a single, high-yielding step. When coupled with ligation at Sec, this transformation provides a new approach to programmed ligations at Ser residues. This new reaction is compatible with a wide range of functionality, including the presence of unprotected amino acid side chains and appended glycans. The utility of the methodology is demonstrated in the rapid synthesis of complex glycopeptide fragments of the epithelial glycoproteins MUC5AC and MUC4 and through the total synthesis of the structured, cysteine (Cys)-free protein eglin C.

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confidence: 99%

Oxidative Deselenization of Selenocysteine: Applications for Programmed Ligation at Serine

et al. 2015

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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.…”

Section: O-acyl Isopeptide Methodsmentioning

confidence: 99%

“…The O-acyl isopeptide of Aβ1-42, which has an ester bond between Gly 25 and Ser 26 ( Fig. 1), was efficiently constructed using SPPS and easily purified by reverse-phase HPLC thanks to the sharp elution profile with reasonable water solubility.…”

Section: O-acyl Isopeptide Of Aβ1-42mentioning

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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“…24 Recently we demonstrated such classic O-to N-acyl migration via various transition states in O-acylated serine and tyrosine isopeptides. 25,26 We now report an experimental and computational study of "traceless" chemical ligation involving O-to N-acyl shift (at Ser and Thr sites) with 8-and 11-membered transition states, involving neither cysteine nor an auxiliary group at the ligation site.…”

Section: -7mentioning

confidence: 99%