- Total Synthesis of the Death Cap Toxin Phalloidin: Atropoisomer Selectivity Explained by Molecular-Dynamics Simulations
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Phallotoxins and amatoxins are a group of prominent peptide toxins produced by the death cap mushroom Amanita phalloides. Phalloidin is a bicyclic cyclopeptide with an unusual tryptathionin thioether bridge. It is a potent stabilizer of filamentous actin and in a fluorescently labeled form widely used as a probe for actin binding. Herein, we report the enantioselective synthesis of the key amino acid (2S,4R)-4,5-dihydroxy-leucine as a basis for the first total synthesis of phalloidin, which was accomplished by two different synthesis strategies. Molecular-dynamics simulations provided insights into the conformational flexibility of peptide intermediates of different reaction strategies and showed that this flexibility is critical for the formation of atropoisomers. By simulating the intermediates, rather than the final product, molecular-dynamics simulations will become a decisive tool in orchestrating the sequence of ring formation reactions of complex cyclic peptides.
- Yao, Guiyang,Joswig, Jan-Oliver,Keller, Bettina G.,Süssmuth, Roderich D.
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supporting information
p. 8030 - 8034
(2019/05/29)
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- An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide
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The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X-ray diffraction analysis suggests that the absolute configuration of the in-tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation.
- Hu, Kuan,Geng, Hao,Zhang, Qingzhou,Liu, Qisong,Xie, Mingsheng,Sun, Chengjie,Li, Wenjun,Lin, Huacan,Jiang, Fan,Wang, Tao,Wu, Yun-Dong,Li, Zigang
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supporting information
p. 8013 - 8017
(2016/09/13)
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- Direct incorporation of unprotected ketone groups into peptides during solid-phase synthesis: Application to the one-step modification of peptides with two different biophysical probes for FRET
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An amino acid bearing an unprotected ketone group, (2S)-aminolevulinic acid, was incorporated into a synthetic peptide using standard Fmoc-based solid-phase methods. The ketone group remained unharmed during the synthesis and provided a uniquely reactive functional group for covalent modification of the peptide. The ketone and the sulfhydryl group of a cysteine residue elsewhere in the peptide were reacted simultaneously with two different biophysical probes, enabling the site-specific installation of a donor and acceptor pair for FRET in one step without the need for differential side chain protection.
- Marcaurelle, Lisa A.,Bertozzi, Carolyn R.
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p. 7279 - 7282
(2007/10/03)
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- Synthesis of 2>Leu-enkephalin and 2,D-Leu5>Leu-enkephalin with High Specific Tritiated Activity in the Leucine Residue
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2>Leu-enkephalin and 2,D-Leu5>Leu-enkephalin (DADLE) labelled with tritium in the leucine residue have been prepared.Synthesis of the precursor peptides, 2,4,5-didehydro-L-Leu5>Leu-enkephalin and 2,4,5-didehydro-D-Leu5>Leu-enkephalin, was carried out by solid-phase synthesis using Fmoc amino acid derivatives, followed by diastereoisomeric separation on HPLC.These peptides were tritiated catalytically to yield DALE with a specific activity of 5.35 TBq mmol-1 and DADLE with that of 5.43 TBq mmol-1, respectively.The distribution of tritium label was investigated by HPLC with a radioisotopic detector following acidic hydrolysis, which confirmed that the tritium label in both labelled peptides was exclusively located at the leucine residue.
- Hasegawa, Hiroshi,Shinohara, Yoshihiko,Baba, Shigeo
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p. 2641 - 2644
(2007/10/02)
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- Synthesis of 2>- and 6>-Locust Adipokinetic Hormone
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The syntheses of 2>- and 6>-locust adipokinetic hormone (LAKH) by the coupling of N-terminal hexapeptides prepared by the solid-phase method with a common C-terminal tetrapeptide synthesised in solution
- Hardy, Paul M.,Sheppard, Paul W.
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p. 723 - 729
(2007/10/02)
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