Synthesis of a biological active β-hairpin peptide by addition of two structural motifs

Fischer, Sabrina; Lamping, Matthias; Gold, Maike; Röttger, Yvonne; Brödje, Dörte; Dodel, Richard; Frantz, Renate; Mraheil, Mobarak Abu; Chakraborty, Trinad; Geyer, Armin

doi:10.1016/j.bmc.2016.11.022

Cited by 9 publications

(11 citation statements)

References 32 publications

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“…The unique cyclic structure of proline and the shortest side chain of glycine made them ideally suited for beta turn 55 . Inspired by such structures, proline and glycine were incorporated to make hairpin peptides (such as (VK) 4 -VD PP T-(KV) 4 –NH 2 , CVLK NG EWHC-NH 2 ), which can be applied for drug release and cell culture 56 , 57 . As residues PP and NG were extensively demonstrated to be the turn sequence of hairpin conformation 58 , 59 , there were 6 and 7 β-hairpin peptides being detected in CRU-NPs and F1-NPs, respectively (see peptides with a yellow background in Fig.…”

Section: Resultsmentioning

confidence: 99%

Small amphipathic peptides are responsible for the assembly of cruciferin nanoparticles

Hong

Akbari

2017

Sci Rep

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Amphipathic peptides are versatile building blocks for fabricating well-ordered nanostructures, which have gained much attention owing to their enormous design possibilities and bio-functionalities. However, using amphipathic peptides from natural proteins to create tunable nanostructures is challenging because of their heterogeneity and great tendency to form aggregates. Here we fabricated two well-defined nanoparticles from cruciferin amphipathic peptides by integrating top-down and bottom-up approach. Alkali hydrolysis (pH 12, 120 °C for 30 min) was introduced to break down intact cruciferin into peptides (top–down). The cruciferin peptides and their fractions were then assembled into nanoparticles (bottom–up) in the presence of calcium ions. The permeate fraction from 10 kDa cut-off membrane formed smaller nanoparticles (F1-NPs) (around 82 nm) than that of unfractionated cruciferin peptides (CRU-NPs, around 185 nm); the electrostatic and hydrophobic interactions were the main driving forces for particle formation. LC-MS/MS analysis characterised that the small amphipathic peptides (Xn1Zn2Xn3Zn4, n1–4 = 0~5), composed of alternating hydrophobic (X) and hydrophilic (Z) amino acid with a length of 5–15 and 5–20 residues for F1-NPs and CRU-NPs, respectively, were responsible for particle formation. Our study established the mechanism of particle formation of the cold gelation is through assembly of amphipathic peptides.

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Section: Resultsmentioning

confidence: 99%

Small amphipathic peptides are responsible for the assembly of cruciferin nanoparticles

Hong

Akbari

2017

Sci Rep

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“…Hop was inserted at the position of Trp into the β‐hairpin motif and, like most other amino acids, is too small or otherwise not qualified to mimic the known Trp 3 side‐chain hydrophobic contact with the Leu 12 δ‐methyl groups. The absence of this contact results in a strong deshielding of the diastereomeric Leu δ‐CH 3 protons . To test this hypothesis and identify metal‐chelation protocols, we synthesized a number of peptides differing by a single side chain.…”

Section: Resultsmentioning

confidence: 99%

Reversible Folding of a β‐Hairpin Peptide by a Metal‐Chelating Amino Acid

Reutzel

Diogo

Geyer

2017

Chemistry A European J

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5-(1-Hydroxy-pyridin-2(1H)-onyl)-l-alanine (Hop) is a N-hydroxy-1,2-pyridone functionalized α-amino acid with the desired metal-chelating properties of DOPA (3,4-dihydroxy phenylalanine) but without its unwanted redox activity. The Fmoc-protected amino acid Fmoc-l-Hop(tBu)-OH (11) was synthesized from glycine phosphonate followed by enzymatic hydrolysis of the methyl ester yielding the Hop l-isomer in 96 % ee. The amino acid 11 is used in automated peptide synthesis for the assembly of a 14mer β-hairpin peptide with the sequence [dsb ]H-CHXETGKHGHKLVC-OH (X=W, l-Hop). While the 10 π electron containing indole side chain of l-Trp in peptide 14 completes the formation of a hydrophobic cluster and results in 90 % folding, the folded fraction is significantly decreased to approximately 30 % for the 6 π electron l-Hop side chain in peptide 16. Metal chelation of Ga reconstitutes the folding of 16 to above 60 % due to the formation of the Ga(16) trimer. The chelation process of 16 is monitored by NMR spectroscopy and the subsequent release of Ga by a competitive metal chelator exemplifies the reversible oligomerization of peptide epitopes by metal chelation, bearing the opportunity to synthesize protein-sized aggregates on the basis of reversible chemistry in water.

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“…In another example, rigidification of a citrulline-containing peptide with a pair of disulfides resulted in inhibitors with improved affinity for anti-citrullinated peptide antibodies. [25] …”

Section: Synthesis Of Bicyclic Peptidesmentioning

confidence: 99%

“…Based on ac rystal structure of vascular endothelial growth factor (VEGF) in complex with VEGF receptor-1 (VEGFR1), Inguimbert et al [24] rationally designed ab icyclic 25mer VEGF antagonist, to mimic three of the VEGF strandsi nvolvedi nt he interaction with the receptor.I na nothere xample, rigidificationo fac itrulline-containing peptide with ap air of disulfides resulted in inhibitors with improved affinity for anti-citrullinated peptide antibodies. [25] Cell-permeable bicyclic peptides have been designed to targeti ntracellular proteins. By screening ac ombinatoriall ibrary,L ian et al discovered ap otent monocyclic peptidei nhibitor (12,F igure 4a)a gainst protein-tyrosine phosphatase 1B (PTP1B).…”

Section: Rational Designmentioning

confidence: 99%

Bicyclic Peptides as Next‐Generation Therapeutics

Rhodes

Pei

2017

Chemistry A European J

135

107

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Bicyclic peptides have greater conformational rigidity and metabolic stability than linear and monocyclic peptides and are capable of binding to challenging drug targets with antibody-like affinity and specificity. Powerful combinatorial library technologies have recently been developed to rapidly synthesize and screen large bicyclic peptide libraries for ligands against enzymes, receptors, and protein-protein interaction targets. Bicyclic peptides have been developed as potential therapeutics against a wide range of diseases, drug targeting agents, imaging/diagnostic probes, and research tools. In this minireview, we provide a summary of the recent progresses on the synthesis and applications of bicyclic peptides.

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Synthesis of a biological active β-hairpin peptide by addition of two structural motifs

Cited by 9 publications

References 32 publications

Small amphipathic peptides are responsible for the assembly of cruciferin nanoparticles

Small amphipathic peptides are responsible for the assembly of cruciferin nanoparticles

Reversible Folding of a β‐Hairpin Peptide by a Metal‐Chelating Amino Acid

Bicyclic Peptides as Next‐Generation Therapeutics

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