title: Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation.
abstract: Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) in comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol of peptidyl prolyl thioesters in NCL without using any thiol-based additives, where the introduction of a 4-mercaptan substituent on the C-terminal proline significantly improves the reactivity of prolyl thioesters via the formation of a bicyclic thiolactone intermediate. The kinetic data indicate that the reaction rate is comparable to that of the reported data of alanyl thioesters, and the mechanistic studies suggest that the ligation of two peptide segments proceeds through an NCL-like pathway instead of a direct aminolysis, which ensures the chemoselectivity and compatibility of various amino acid side chains. This 4-mercaptoprolyl thioester-based protocol also allows an efficient one-pot ligation-desulfurization procedure. The utility of this method has been further demonstrated in the synthesis of a proline-rich region of Wilms tumor protein 1.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gui
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Lingqi
authors.initials: L
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Yaohao
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , 38 Xueyuan Road, Haidian District, Beijing 100191, China.
authors.forename: Suwei
authors.initials: S
authors.lastname: Dong
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D007700:Kinetics; D010455:Peptides / Q000737:chemistry*; D011392:Proline / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D025721:WT1 Proteins / Q000737:chemistry
chemical_list: D000596:Amino Acids; D010455:Peptides; D013438:Sulfhydryl Compounds; D025721:WT1 Proteins; D011392:Proline