“Triazole Bridge”: Disulfide‐Bond Replacement by Ruthenium‐Catalyzed Formation of 1,5‐Disubstituted 1,2,3‐Triazoles

Empting, Martin; Avrutina, Olga; Meusinger, Reinhard; Fabritz, Sebastian; Reinwarth, Michael; Biesalski, Markus; Voigt, Stephan; Buntkowsky, Gerd; Kolmar, Harald

doi:10.1002/anie.201008142

Cited by 120 publications

(112 citation statements)

References 67 publications

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“…The extent of splitting of the diastereotopic Hα’s of Gly correlates with hairpin folding at the turn. 15 Both non-cyclic and cyclic peptides of Term and Term-rev have a glycine splitting value of 0.74 ppm, indicating no drastic change in hairpin folding. This lack in difference is most likely due to the position of the CuAAC.…”

Section: Resultsmentioning

confidence: 99%

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Positional effects of click cyclization on β-hairpin structure, stability, and function

Park

Waters

2013

Org. Biomol. Chem.

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The use of the copper (I)-assisted azide-alkyne cycloaddition (CuAAC, or “click” reaction) as a method of β-hairpin stabilization was investigated at several different positions to determine the impact on hairpin structure and function, including hydrogen bonded sites, non-hydrogen bonded sites, and at the peptide termini. The role of the turn sequence in the peptide and the chain length of the azied were also investigated. It was determined that the CuAAC reaction was a suitable method for locking in β-hairpin structure in peptides possessing either the type I’ turn, VNGO and the type II’ turn, VpGO. Moreover, all cyclic variants exhibited improved thermal stability and resistance to proteolysis as compared to the non-cyclic peptides, regardless of the position in the strand. Additionally, the function of the CuAAC cyclized peptides was not altered as exhibited by similar binding affinities for ATP as the WKWK peptide. These studies provided a comprehensive method for CuAAC cyclization of β-hairpin peptides, which could further be utilized in the inhibition of protein-protein and protein-nucleic acid interactions.

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Section: Resultsmentioning

confidence: 99%

“…14 This study not only demonstrates the structural advantages of the CuAAC in β-hairpins but also the preservation of function and enhanced protection to proteolysis. Thus, CuAAC cyclization 15 of β-hairpins is a general and promising approach to the disruption of protein-protein and protein-nucleic acid interactions.…”

Section: Introductionmentioning

confidence: 99%

Positional effects of click cyclization on β-hairpin structure, stability, and function

Park

Waters

2013

Org. Biomol. Chem.

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“…first used the 1,5-disubstituted 1,2,3-triazole as a surrogate of a disulfide bond [28]. The 1,5-disubstituted 1,2,3-triazole was generated in a ruthenium(II)-catalysis variation (RuAAC) of the CuAAC.…”

Section: 123-triazoles As Surrogates For Unstable Bondsmentioning

confidence: 99%

Click Chemistry in Peptide-Based Drug Design

2013

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Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.

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“…Additionally, these moieties can substitute disulfide bonds resulting in redox-stable constructs. Although these building blocks has not been yet applied to tridisulfide peptides, their viability was demonstrated using the scaffold of single-disulfide sunflower trypsin inhibitor I (SFTI-I) [126,127].…”

Section: Box 4: Triazolyl-bearing Peptidomimetics For Miniprotein Engmentioning

confidence: 99%

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

Avrutina

2016

Advances in Experimental Medicine and Biology

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Peptides with the cystine-knot architecture, often termed knottins, are promising scaffolds for biomolecular engineering. These unique molecules combine diverse bioactivities with excellent structural, thermal, and proteolytical stability. Being different in the composition and structure of their amino acid backbone, knottins share the same core element, namely cystine knot, which is built by six cysteine residues forming three disulfides upon oxidative folding. This motif ensures a notably rigid framework that highly tolerates both rational and combinatorial changes in the primary structure. Being accessible through recombinant production and total chemical synthesis, cystine-knot miniproteins can be endowed with novel bioactivities by variation of surface-exposed loops and incorporation of non-natural elements within their non-conserved regions towards the generation of tailor-made peptidic compounds. In this chapter the topology of cystine-knot peptides, their synthesis and applications for diagnostics and therapy is discussed.

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“Triazole Bridge”: Disulfide‐Bond Replacement by Ruthenium‐Catalyzed Formation of 1,5‐Disubstituted 1,2,3‐Triazoles

Cited by 120 publications

References 67 publications

Positional effects of click cyclization on β-hairpin structure, stability, and function

Positional effects of click cyclization on β-hairpin structure, stability, and function

Click Chemistry in Peptide-Based Drug Design

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

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