On-bead cyclization in a combinatorial library of 15,625 octapeptides

Fluxà, Viviana S.; Reymond, Jean‐Louis

doi:10.1016/j.bmc.2008.01.045

Cited by 27 publications

(19 citation statements)

References 40 publications

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“…15 Since neither t -butyl protected Ser nor β-branched Val and Ile residues were overrepresented among the poorly cyclizing sequences, the exceptional bulkiness of the t-butyl protected Thr likely reduced the nucleophilicity of the N-terminal amine. A unique feature of Pbf-protected Arg and Boc-protected Lys is that their side chains are capable of forming bidentate hydrogen bonds with each other and with the carboxyl group (Figure 4a–c).…”

Section: Resultsmentioning

confidence: 99%

“…The ability of proline to accommodate cis - peptide bonds presumably brings the peptide N- and C-termini close to each other and facilitates intramolecular lactamization. 15 However, its secondary amine group is more hindered and thus less nucleophilic than the α-amine of other proteinogenic amino acids.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, Fluxa and Reymond reported an elegant study of peptide cyclization efficiency by screening a resin-bound library of 15,625 octapeptides [XXXXXKXE-(β-Ala-β-Ala-TentaGel)-OAll]. 15 They found that fast-cyclizing sequences often contained turn elements (e.g., Pro), whereas slow-cyclizing sequences were rich in basic and polar residues, in particular an N-terminal Thr and an Arg-His-Ser motif next to the N-terminal residue. However, their study was limited to octapeptides and employed only 5 different amino acids at each of the six random positions for a total of 15 different amino acids in the library.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Global Analysis of Peptide Cyclization Efficiency

2013

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“…We next examined the scope of the microfluidic process by varying some internal residues, the C-terminal amino acid bearing the SEAE functionality, and peptide length. Concerning the role of internal residues, several studies have shown that a proline can favor the backbone cyclization of protected peptides in organic solvents by classical activation procedures 44 . Indeed, the cis conformation of the peptide bond to proline is significantly more frequent (typically ~9% for Glu-Pro as in peptide 4c ) than for the other amino acids (<0.1%) 45 , thereby introducing a kink in the peptide chain and bringing the reactive ends closer in space.…”

Section: Resultsmentioning

confidence: 99%

Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides

Ollivier¹,

Toupy²,

Hartkoorn³

et al. 2018

Nat Commun

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Cyclic peptide-based therapeutics have a promising growth forecast that justifies the development of microfluidic systems dedicated to their production, in phase with the actual transitioning toward continuous flow and microfluidic technologies for pharmaceutical production. The application of the most popular method for peptide cyclization in water, i.e., native chemical ligation, under microfluidic conditions is still unexplored. Herein, we report a general strategy for fast and efficient peptide cyclization using native chemical ligation under homogeneous microfluidic conditions. The strategy relies on a multistep sequence that concatenates the formation of highly reactive S-(2-((2-sulfanylethyl)amino)ethyl) peptidyl thioesters from stable peptide amide precursors with an intramolecular ligation step. With very fast ligation rates (<5 min), even for the most difficult junctions (including threonine, valine, isoleucine, or proline), this technology opens the door toward the scale-independent, expedient preparation of bioactive macrocyclic peptides.

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“…7 Numerous strategies have been developed to mitigate these problems, including the incorporation of D-configured 8 and non-proteinogenic amino acids, 9 pseudo-peptide bonds and conformational constraints. 10,11 Each of these features is seen in peptide-derived macrocyclic natural products, which often possess markedly different properties relative to their acyclic precursors. With macrocycles as a central theme, we have sought to expand upon existing methods for large ring formation.…”

Section: Introductionmentioning

confidence: 99%

Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan

2013

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Macrocyclic peptidomimetics are valuable in research and serve as lead compounds in drug discovery efforts. New methods to prepare such structures are of considerable interest. In this pilot study, we show that an organic template harboring a latent cinnamyl cation participates in novel Friedel-Crafts macrocyclization reactions with tryptophan. Upon joining the template to Trp-Trp-Tyr, a single operation efficiently generates eight unique macrocycles. Each has been isolated and thoroughly characterized. Product distribution as a function of Brønsted and/or Lewis acidic conditions was explored, and outcomes were compared to rearrangements induced within a corresponding tyrosine-linked cyclic ether. The solution structure of a new macrocyclic pyrroloindoline was solved using a combination of two-dimensional NMR methods and molecular mechanics simulations. Template-induced structural diversification of peptide sequences harboring aromatic residues has potential to create myriad macrocycles that target surfaces involved in protein-protein interactions.

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On-bead cyclization in a combinatorial library of 15,625 octapeptides

Cited by 27 publications

References 40 publications

Global Analysis of Peptide Cyclization Efficiency

Global Analysis of Peptide Cyclization Efficiency

Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides

Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan

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