Native Chemical Ligation at Valine: A Contribution to Peptide and Glycopeptide Synthesis

Chen, Jin; Wan, Qian; Yuan, Yu; Zhu, Jianglong

doi:10.1002/anie.200803523

Cited by 210 publications

(140 citation statements)

References 31 publications

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“…This step is typically followed by several protecting group manipulations, including hydrolysis of the thioacetate moiety, to enable protection of the thiol handle as an asymmetric disulfide or the corresponding S-trityl (Trt) derivative, both of which are compatible with standard conditions employed in Fmoc-strategy SPPS. [19] This overall synthetic strategy has been employed for the synthesis of several thiol-derived amino acids, including b-thiol phenylalanine (Phe), [20] g-thiol Val, [21] g-thiol lysine (Lys), [22] d-thiol Lys, [23] g-thiol threonine (Thr), [24] b-thiol leucine (Leu), [25] g-thiol Pro, [26] g-thiol glutamine (Gln), [27] and b-thiol arginine (Arg). [8d] In 2007, Crich and Banerjee prepared b-thiol Phe building block 3 [20a] for use in ligation-desulfurization chemistry in a 9-step synthesis from L-Phe methyl ester 4 (Scheme 3).…”

Section: Synthesis Of Thiol-derived Amino Acids Through Nucleophilic mentioning

confidence: 99%

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Malins

Payne

2015

Aust. J. Chem.

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Native chemical ligation is a powerful tool for the convergent assembly of homogeneous peptide and protein targets from unprotected peptide fragments. The method involves the chemoselective coupling of a peptide thioester with a peptide bearing an N-terminal cysteine (Cys) residue and is mediated by the nucleophilic Cys thiol functionality. A widely adopted extension of the technique for the disconnection of protein targets at alanine (Ala) ligation junctions has been the application of post-ligation desulfurization protocols for the mild removal of the Cys thiol moiety. Recently, attention has turned to the construction of synthetic amino acid building blocks bearing suitably positioned b-, g-, or d-thiol ligation auxiliaries with a view to expanding the scope of the ligation-desulfurization manifold. To date, several thiol-derived amino acids have been prepared, greatly increasing the generality and flexibility of chemoselective ligation technologies for the chemical synthesis of diverse protein targets. This review will highlight the current synthetic approaches to these important amino acid building blocks.

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Section: Synthesis Of Thiol-derived Amino Acids Through Nucleophilic mentioning

confidence: 99%

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Malins

Payne

2015

Aust. J. Chem.

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“…can be converted to Phe (43), Val (44,45), Thr (46) residues by the similar desulfurization reaction, was synthesized and used for the ligation. The problem using these methods lies in that the catalyst easily adsorbs peptides and that demethanethiolation of Met residue sometimes occurs.…”

Section: Scheme 5 Schemementioning

confidence: 99%

Progress in the Ligation Chemistry for Glycoprotein Synthesis

Hojo

Katayama

Nakahara

2010

TIGG

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“…Such methods are not ideal for the generation of analogs (30)(31)(32)(33). It was recognized that enhancement of the power of chemical synthesis for such objectives, including that of hPTH itself, could be accomplished by extending the reach of the underlying elegant concept of NCL (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). To this end, we report a pleasing and encouraging example wherein these recent findings have been pooled such that the molecule hPTH can be conveniently assembled from small synthetic peptide fragments.…”

mentioning

confidence: 94%

“…(2,3). However, given the relative scarcity of cysteine residues in nature, a clear impetus arises for the realization of new NCL capabilities (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 99%

Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH)

Shang

Tan

Danishefsky

2011

Proc. Natl. Acad. Sci. U.S.A.

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The power of chemical synthesis of large cysteine-free polypeptides has been significantly enhanced through the use of nonproteogenic constructs which bear strategically placed thiol groups, enabling native chemical ligation. Central to these much expanded capabilities is the specific, radical-induced, metal-free dethiolation, which can be accomplished in aqueous medium. Anticipating this type of problem, our laboratory (9, 11, 14, 17) and others (5-7, 10) have developed strategies by which to accomplish ligation at a range of noncysteine amino acid residues. The logic of our approach is outlined in Fig. 1. The N-terminal peptide, D, to be ligated is equipped with an N-terminal sulfurbearing amino acid surrogate, A, itself prepared by synthesis and coupled, by a suitable method, to the peptide B. In this way, N-terminal ligation candidate D is ready for coupling with C-terminal acyl donating peptide C (usually a thioester). Ligation product E can be maintained as such, thereby affording a specifically placed thiol group in a nonnatural context. Theoretically, de-thiolation of E will produce F wherein the "R" group had been governed by the synthetically derived A. In principle, the strategy shown in Fig. 1 is of universal scope.Studies using a variety of model peptides have demonstrated the fragment-coupling capability of the cysteine-free strategy. Here, in this paper, we seek to examine the general applicability of this strategy to the total synthesis of cysteine-poor proteins. Human Parathyroid Hormone (hPTH) is chosen to serve as a model molecule because of its representativeness in terms of amino acid composition and its therapeutic value. hPTH is a biological messenger that is secreted by the parathyroid glands as a peptide containing 84 amino acids (18,19). Upon binding to its receptor, hPTH can enhance the concentration of calcium (Ca 2þ ) in the blood (20). Because of their important physiological roles, hPTH and one of its fragments, hPTH (1-34), are now given (by subcutaneous injection) for the treatment of hypoparathyroidism and osteoporosis in men, as well as for postmenopausal women at high risk of fracture (21-23). Not unlike most other hormone drugs, the recombinant hPTH therapeutics have very short half-lives in the human body and need to be administered at least once a day (24, 25). The need for continuous daily subcutaneous injection is an obvious disadvantage which serves to compromise use of the hormone. Clearly, the production of more stable forms of hPTH, where "pharmacolability" is attenuated without undercutting biological activity, would be of great interest (26). It is also of interest to interrogate the consequences of employing nonproteogenic inserts (27). While this goal can be accomplished by cleverly designed recombinant methods, chemical synthesis could well be more convenient for servicing the initial production of probe structures for such structure-activity relationship (SAR) evaluations (28,29). Previously, the chemical synthesis of hPTH required either the solid phase synthes...

show abstract

Native Chemical Ligation at Valine: A Contribution to Peptide and Glycopeptide Synthesis

Cited by 210 publications

References 31 publications

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Progress in the Ligation Chemistry for Glycoprotein Synthesis

Application of the logic of cysteine-free native chemical ligation to the synthesis of Human Parathyroid Hormone (hPTH)

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