Influence of proline and β-turn mimetics on the cyclization of penta- and hexapeptides

Klose, Jana; Ehrlich, Angelika; Bienert, Michael

doi:10.1007/bf02443454

Cited by 8 publications

(10 citation statements)

References 14 publications

(5 reference statements)

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“…The challenge associated with cyclization of tetra- and pentapeptides in the all-L-configuration is well documented in the literature. 24 Incorporation of D-amino acids (which reduce the steric hindrance) or β-turn motifs (e.g., Gly-Pro and Sar-Pro) has been shown to facilitate the formation of these small rings. 12–14, 24 It should be noted that formation of still smaller rings (i.e., cyclodipeptide or 2,5-diketopiperazine) is relatively straightforward.…”

Section: Resultsmentioning

confidence: 99%

Global Analysis of Peptide Cyclization Efficiency

2013

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Cyclic peptides are of considerable interests in drug discovery and nanotechnology. However, macrocyclization of peptides and other compounds has often been perceived as synthetically challenging and the cyclization yields are affected by several factors including the ring size, peptide sequence, and the reaction conditions. Through the screening of combinatorial peptide libraries, we analyzed the cyclization efficiency of >2 million peptide sequences to determine the effect of ring size, peptide sequence, and solvent on the backbone (N-to-C) cyclization of peptides. Our results show that on-resin cyclization of medium- and large-sized rings (cyclohexapeptides and above) with PyBOP is essentially quantitative for ≥99.96% of the sequences, with small amounts of dimer formation observed for <4% of these sequences. Cyclization of small rings (cyclotetrapeptides and cyclopentapeptides) is considerably more difficult and accompanied by significant cyclic dimer formation. Peptides that are difficult to cyclize are generally rich in Lys(Boc) and Arg(Pbf) residues as well as sterically hindered residues [e.g., Thr(tBu)] at the N-terminus. The majority of these difficult sequences can be cyclized to completion by the addition of aqueous additives to the cyclization reaction.

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Section: Resultsmentioning

confidence: 99%

Global Analysis of Peptide Cyclization Efficiency

2013

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“…We selected a pentapeptide scaffold to carry out the cyclization since this number of amino acids yields macrocycles with some rigidity, after amide bond formation between the N ‐ and C ‐ termini. D‐Proline was selected as C ‐terminal amino acid (i.e., anchorage point to the resin) to favor cyclization in solution by inducing a turn conformation . Lysine incorporation provided good results in terms of passive diffusion permeability and poor membrane retention, as well as non‐cytotoxicity in HeLa cells .…”

Section: Resultsmentioning

confidence: 99%

Bromotryptophans and their incorporation in cyclic and bicyclic privileged peptides

et al. 2018

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While revisiting biologically active natural peptides, the importance of the tryptophan residue became clear. In this article, the incorporation of this amino acid, brominated at different positions of the indole ring, into cyclic peptides was successfully achieved. These products demonstrated improved properties in terms of passive diffusion, permeability across membranes, biostability in human serum and cytotoxicity. Moreover, these brominated tryptophans at positions 5, 6, or 7 proved to be compatible as building blocks to prepare bicyclic stapled peptides by performing on-resin Suzuki-Miyaura cross-coupling reactions.

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“…Recent advances in the area of structural modeling have increased our ability to design bioactive cyclic peptides and peptidomimetics, yet the cyclization step in the actual synthesis is often troublesome, particularly for head‐to‐tail cyclization of small (< 7 residues) peptides (5). Several cases have been reported in the literature in which cyclization yields depend strongly on the sequence of the linear peptide precursor (5–9). Moreover, several linear precursors, all leading to the same cyclic product, often showed highly variable yields in the cyclization (7–9).…”

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confidence: 99%

“…Several cases have been reported in the literature in which cyclization yields depend strongly on the sequence of the linear peptide precursor (5–9). Moreover, several linear precursors, all leading to the same cyclic product, often showed highly variable yields in the cyclization (7–9).…”

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confidence: 99%

“…The peptides considered are of the general structure Fmoc‐[Ala(C1) 1 ‐Xaa 2 ‐Yaa 3 ‐Ala(N2) 4 ]‐NH 2, where Ala(C1) = HN(CH 2 COOH)Ala and Ala(N2) = HN((CH 2 ) 2 NH 2 )Ala are the N‐substituted alanines at positions 1 and 4 through which backbone cyclization is achieved (1). In previous studies, cyclization tendencies were inferred from the formation yields of the desired cyclic product relative to the formation of the higher cyclic oligomers, after reactions had been allowed to reach completion (5–7). In contrast, in this study, progression of the cyclization reaction was monitored directly, yielding the kinetics of change in the amounts of both reactant and products.…”

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confidence: 99%

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Study on the cyclization tendency of backbone cyclic tetrapeptides

Besser¹,

Reißmann²,

Olender³

et al. 2000

The Journal of Peptide Research

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The cyclization kinetics of five backbone-cyclic tetrapeptides was investigated both experimentally and computationally. The aim was to both accurately measure the cyclization rates in solution and develop a method that efficiently estimates the relative cyclization tendencies computationally. Progression of the cyclization reaction was monitored directly, yielding the kinetics of changes in the amounts of the linear precursor and the products. These measurements were used to calculate the reaction rates; the results were consistent with a first-order reaction kinetics. In order to predict the cyclization rates computationally, the conformation space of the linear precursors was mapped and used to construct an approximate partition function. We assumed that the cyclization tendency was correlated with the relative probability of being found in a cyclization-prone conformation of the backbone, this probability was estimated from the partition function. The results supported this assumption and demonstrated that, within reasonable accuracy, we are able to predict the relative cyclization tendencies of the peptides measured.

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Influence of proline and β-turn mimetics on the cyclization of penta- and hexapeptides

Cited by 8 publications

References 14 publications

Global Analysis of Peptide Cyclization Efficiency

Global Analysis of Peptide Cyclization Efficiency

Bromotryptophans and their incorporation in cyclic and bicyclic privileged peptides

Study on the cyclization tendency of backbone cyclic tetrapeptides

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