Fragment Condensation of C‐Terminal Pseudoproline Peptides without Racemization on the Solid Phase

Heinlein, Christian; Silva, Daniel Varón; Tröster, Andrea; Schmidt, Jan Philipp; Gross, Angelina; Unverzagt, Carlo

doi:10.1002/anie.201101270

Cited by 43 publications

(30 citation statements)

References 27 publications

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“…Pseudo-prolines ( Pro) are serine-or theonine-derived oxazolidines or cysteine-derived thiozolidines with proline-like ring structures Fig. A fragment condensation of the complex RNase 1-39 glycopeptide made with Pro fragments was carried out successfully using SPPS without racemization [19]. A fragment condensation of the complex RNase 1-39 glycopeptide made with Pro fragments was carried out successfully using SPPS without racemization [19].…”

Section: Improving Chemical Synthesismentioning

confidence: 99%

“…Peptide sequences produced by recombinant methods were further altered chemically and/or enzymatically. In another example of complicated semi-synthesis, the aforementioned Pro RNase 1-39 glycopeptide fragment condensation product was coupled to a recombinantly-expressed RNase 40-124 peptide fragment using native chemical ligation, producing the full protein [19]. Liraglutide is an analogue of glucagon-like peptide 1, recombinantly expressed in yeast with a 16-carbon lipid chain chemically attached to Lys 26 via a glutamic acid spacer [41,42].…”

Section: Combined Chemical and Biological Synthesis: Peptide Semisyntmentioning

confidence: 99%

See 1 more Smart Citation

Peptides As Therapeutics with Enhanced Bioactivity

Goodwin

Simerská

Tóth

2012

CMC

151

104

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The development of techniques for efficient peptide production renewed interest in peptides as therapeutics. Numerous modifications for improving stability, transport and affinity profiles now exist. Several new adjuvant and carrier systems have also been developed, enhancing the immunogenicity of peptides thus allowing their development as vaccines. This review describes the established and experimental approaches for manufacturing peptide drugs and highlights the techniques currently used for improving their drug like properties.

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Section: Improving Chemical Synthesismentioning

confidence: 99%

Section: Combined Chemical and Biological Synthesis: Peptide Semisyntmentioning

confidence: 99%

Peptides As Therapeutics with Enhanced Bioactivity

Goodwin

Simerská

Tóth

2012

CMC

151

104

View full text Add to dashboard Cite

show abstract

“…We next evaluated the feasibility of a more challenging proposition, namely, the possibility of an iterative chemoselective solidphase fragment coupling (SPFC) via isonitrile-mediated amidation. Due to the high levels of convergence, SPFC is, in principle, an attractive strategy for the synthesis of large peptides and/or peptides with "difficult" sequences (34)(35)(36)(37)(38)(39)(40). Moreover, SPFC may offer considerable advantages in allowing for interim purification, which should simplify obtaining homogeneous end product.…”

Section: % (mentioning

confidence: 99%

Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles

Wang

2013

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

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The synthesis of polypeptides on solid phase via mediation by isonitriles is described. The acyl donor is a thioacid, which presumably reacts with the isonitrile to generate a thio-formimidate carboxylate mixed anhydride intermediate. Applications of this chemistry to reiterative solid-phase peptide synthesis as well as solid-phase fragment coupling are described.A mide bond formations are arguably among the most important constructions in organic chemistry (1, 2). The centrality of the amide linkage, as found in polypeptides and proteins, in the maintenance of life hardly needs restatement. Numerous strategies, resulting in a vast array of protocols to synthesize biologically active polypeptides and proteins, have been demonstrated (3, 4). Central to reiterative polypeptide bond formations was the discovery and remarkable development of solid-phase peptide synthesis (SPPS) (5, 6). The extraordinary impact of SPPS in fostering enhanced access to homogeneous polypeptides is clear to everyone in the field.As we have described elsewhere, by classical, mechanistic reasoning, we were led to conjecture about some hithertounexplored possibilities relevant to the chemistry of isonitriles (7)(8)(9)(10)(11)(12)(13)(14). It was anticipated that isonitriles might be able to mediate the acylation of amines, thus giving rise to amides (15). Early experiments focused on free carboxylic acids as the acylating agents. As our studies progressed, it was found that the combination of thioacids, amines, and isonitriles leads to the efficient formation of amide bonds under stoichiometric or nearstoichiometric conditions (7-13, 16, 17). Although there remain unresolved issues of detail and nuance, the governing mechanism for amide formation under these conditions involves reaction of the thioacid, 1, with an isonitrile, 2, to generate a thio-formimidate carboxylate mixed anhydride (thio-FCMA), 3, which is intercepted by the "acyl-accepting" amine to generate amide, 5, and thioformamide, 6 (Fig. 1). The efficiency of the amidation was further improved through the use of hydroxybenzotriazole (HOBt) (18), which could well give rise to HOBt ester 7, although this pathway has not been mechanistically proven.The potentialities of the isonitrile-mediated amidation method were foreshadowed via its application to the synthesis of cyclosporine (19). The power of the method was particularly well demonstrated in the context of our recent total synthesis of oxytocin (OT) (20), wherein isonitrile mediation was used in each of the peptide bond constructions, leading to the synthesis of the hormone in high yield and excellent purity. This nonapeptide is involved in a range of biological functions including parturition and lactation (21,22). Signaling of OT to its receptor (OTR) is apparently an important factor in quality maintenance of various CNS functions (23). The ability to synthesize such modestly sized, but bio-impactful peptides in both native (wild-type) form, and as strategically modified variants, is one of the current missions of our labo...

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“…We preferred a 7+4 approach which would involve assembly of the protected N ‐terminal fragment and the macrocyclic core. This enables incorporation of an Ile‐Ser pseudo‐ proline dipeptide at the C ‐terminus, to mitigate the potential for epimerisation at l ‐Ser 7 during activation …”

Section: Introductionmentioning

confidence: 99%

The impact of backbone N‐methylation on the structure‐activity relationship of Leu₁₀‐teixobactin

Velkov

Swarbrick

Hussein

et al. 2019

Journal of Peptide Science

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Antimicrobial resistance is a serious threat to global human health; therefore, new anti‐infective therapeutics are required. The cyclic depsi‐peptide teixobactin exhibits potent antimicrobial activity against several Gram‐positive pathogens. To study the natural product's mechanism of action and improve its pharmacological properties, efficient chemical methods for preparing teixobactin analogues are required to expedite structure‐activity relationship studies. Described herein is a synthetic route that enables rapid access to analogues. Furthermore, our new N‐methylated analogues highlight that hydrogen bonding along the N‐terminal tail is likely to be important for antimicrobial activity.

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Fragment Condensation of C‐Terminal Pseudoproline Peptides without Racemization on the Solid Phase

Cited by 43 publications

References 27 publications

Peptides As Therapeutics with Enhanced Bioactivity

Peptides As Therapeutics with Enhanced Bioactivity

Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles

The impact of backbone N‐methylation on the structure‐activity relationship of Leu₁₀‐teixobactin

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Fragment Condensation of C‐Terminal Pseudoproline Peptides without Racemization on the Solid Phase

Cited by 43 publications

References 27 publications

Peptides As Therapeutics with Enhanced Bioactivity

Peptides As Therapeutics with Enhanced Bioactivity

Solid-phase peptide synthesis and solid-phase fragment coupling mediated by isonitriles

The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

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Product

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The impact of backbone N‐methylation on the structure‐activity relationship of Leu₁₀‐teixobactin