Pseudo-prolines in peptide synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides

Wöhr, Torsten; Mutter, Manfred

doi:10.1016/0040-4039(95)00667-2

Cited by 73 publications

(26 citation statements)

References 7 publications

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“…These modified amino acid residues were introduced by Mutter and coworkers as temporary protecting groups for peptide synthesis and were found to exert a pronounced effect on the peptide backbone conformation. [1,2] The oxazolidine derivatives are now extensively used as tools to impart better solubility to a growing peptide chain in solid-phase synthesis because they prevent aggregation of growing peptide chains [3,4] and have been found to significantly increase the yields of difficult peptide sequences [5][6][7][8][9] by improving solvation and peptide coupling kinetics. This is attributed to a conformational preference for cis-amide bond formation.…”

Section: Introductionmentioning

confidence: 99%

Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides

et al. 2009

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The conformations of 14 threonine-derived pseudoproline-containing dipeptides (including four d-allo-Thr derivatives) have been investigated by NMR. In solution, the major conformer observed for all dipeptides is that in which the amide bond between the pseudoproline and the preceding amino acid is cis. For dipeptides in which the N-terminus is protected, the ratio of cis-to trans-conformers does not depend significantly on the side chain of the N-terminal amino acid, or the stereochemistry of the Thr residue. However, for dipeptides bearing a free N-terminus, there are significant differences in the ratios of cis-to trans-conformers depending on the side chain present. Three dipeptides were crystallized and their X-ray structures determined. In two cases, (benzyloxycarbonyl (Cbz)-Val-Thr(ΨMe,Mepro)-OMe and Cbz-ValThr(ΨMe,Mepro)-OH), the dipeptides adopt a trans-conformation in the solid state, in contrast to the structures observed in solution. In the third case, (9-fluorenylmethoxycarbonyl (Fmoc)-Val-d-alloThr(ΨMe,Mepro)-OH), a cis-amide geometry is observed. These structural differences are attributed to crystal-packing interactions. The conformations of 14 threonine-derived pseudoproline-containing dipeptides (including four d-allo-Thr derivatives) have been investigated by NMR. In solution, the major conformer observed for all dipeptides is that in which the amide bond between the pseudoproline and the preceding amino acid is cis. For dipeptides in which the N-terminus is protected, the ratio of cis-to trans-conformers does not depend significantly on the side chain of the N-terminal amino acid, or the stereochemistry of the Thr residue. However, for dipeptides bearing a free N-terminus, there are significant differences in the ratios of cis-to trans-conformers depending on the side chain present. Three dipeptides were crystallized and their X-ray structures determined. In two cases, (benzyloxycarbonyl (Cbz)-Val-Thr( Me,Me pro)-OMe and Cbz-Val-Thr( Me,Me pro)-OH), the dipeptides adopt a trans-conformation in the solid state, in contrast to the structures observed in solution. In the third case, (9-fluorenylmethoxycarbonyl (Fmoc)-Val-d-allo-Thr( Me,Me pro)-OH), a cis-amide geometry is observed. These structural differences are attributed to crystal-packing interactions.

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Section: Introductionmentioning

confidence: 99%

Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides

et al. 2009

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“…The solubility can be improved by introducing at appropriate positions of the sequence backbone protection [45][46][47] or oxazolidine and thiazolidine derivatives of Ser, Thr, and Cys. 48,49 This, because their presence in the sequence interrupt ␤-sheet formation.…”

Section: Purification Of Protected Segmentsmentioning

confidence: 95%

9-Fluorenylmethyloxycarbonyl/tbutyl-based convergent protein synthesis

Barlos

Gatos

1999

Biopolymers

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Besides linear solid phase peptide synthesis, segment condensation in solution and chemical ligation, convergent peptide synthesis (CPS) was developed in order to enable the efficient preparation of complex peptides and small proteins. According to this synthetic strategy, solid phase synthesized and suitably protected peptide fragments corresponding to the entire peptide/protein‐sequence are condensed on a solid support or in solution, to the target protein. This review summarizes CPS performed utilizing the mild 9‐fluorenylmethyloxycarbonyl/tbutyloxycarbonyl‐based protecting scheme for the amino acids. © 1999 John Wiley & Sons, Inc. Biopoly 51: 266–278, 1999

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Section: Internal Modificationsmentioning

confidence: 99%

“…Further strategies aiming to decrease on-resin aggregation during SPPS include the use of pseudoprolines Wohr and Mutter, 1995) or O-acyl isopeptides (Horikawa et al, 1998) (depsipeptides) (Figure 4). Mutter's lab introduced pseudoprolines incorporating them into a sequence with numerous building blocks being commercially available Wohr and Mutter, 1995). The cyclic oxazolidine (Ser, Thr) thiazolidine (Cys) ring system shows structural similarities with Pro, resulting in a "kink" conformation within the growing peptide chain preventing aggregation, self-association and a β-sheet formation (Wohr et al, 1996).…”

Section: Internal Modificationsmentioning

confidence: 99%

Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides

Mueller

Baumruck

Zhdanova

et al. 2020

Front. Bioeng. Biotechnol.

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Solid phase peptide synthesis (SPPS) provides the possibility to chemically synthesize peptides and proteins. Applying the method on hydrophilic structures is usually without major drawbacks but faces extreme complications when it comes to "difficult sequences." These includes the vitally important, ubiquitously present and structurally demanding membrane proteins and their functional parts, such as ion channels, G-protein receptors, and other pore-forming structures. Standard synthetic and ligation protocols are not enough for a successful synthesis of these challenging sequences. In this review we highlight, summarize and evaluate the possibilities for synthetic production of "difficult sequences" by SPPS, native chemical ligation (NCL) and follow-up protocols.

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Pseudo-prolines in peptide synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides

Cited by 73 publications

References 7 publications

Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides

Solid-State and Solution-Phase Conformations of Pseudoproline-Containing Dipeptides

9-Fluorenylmethyloxycarbonyl/tbutyl-based convergent protein synthesis

Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides

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