Synthesis of Bicyclic Peptides

Karskela, Tuomas; Virta, Pasi; Lönnberg, Harri

doi:10.2174/157017906777934917

Cited by 14 publications

(10 citation statements)

References 42 publications

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“…3A) using lactam staples that incorporate commercially available amino acids. [19] Several related classes of peptide bicycles have been previously reported, [20] but there are very few reports of head-to-tail cyclic, lactam-stapled peptides. [21] These few reports have noted that the order in which macrocycles are closed has a large impact on overall yield, and that solution-phase cyclization was often needed to successfully close the second macrocycle.…”

Section: Resultsmentioning

confidence: 99%

Peptide Bicycles that Inhibit the Grb2 SH2 Domain

Quartararo

Kritzer

2012

ChemBioChem

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Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples, producing peptide bicycles with higher affinity, selectivity, and resistance to degradation. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homology 2 (SH2) domain of growth-factor-bound protein 2 (Grb2). Several homodetic peptide bicycles were synthesized entirely on-resin with high yields. Two rounds of iterative design produced peptide bicycle BC1, which is 60-fold more potent than G1 and 200-fold more selective. Also, BC1 is completely intact after 24 hours in buffered human serum, conditions under which G1 is completely degraded. Our peptide bicycle approach holds promise for the development of selective inhibitors of SH2 domains and other pTyr-binding proteins, as well as inhibitors of many other protein-protein interactions.

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Section: Resultsmentioning

confidence: 99%

Peptide Bicycles that Inhibit the Grb2 SH2 Domain

Quartararo

Kritzer

2012

ChemBioChem

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“…Fmoc-GlyWang resin (loading: 0.56 mmol/g) was purchased from Fluorochem UK. NMR data were acquired in DMSO-d 6 at 298 K using a Bruker AvanceII 400 MHz NMR spectrometer. Proton resonances were assigned using TOCSY and HSQC data.…”

Section: Methodsmentioning

confidence: 99%

“…The use of standard amino acid building blocks furthermore ensures relatively low toxicity and unproblematic metabolism, which is one key advantage of peptides when considering therapeutic use. 5 Surprisingly, relatively little attention has been paid to a systematic exploration of graph based peptide design, except for the preparation of bi-or polycyclic peptides using side chain cross-links 6 as found in cysteine knot proteins 7 and lantibiotics. 8 We have shown that peptide equivalents of multi-branched graphs can be prepared in good yields and purities by solid phase peptide synthesis (SPPS), a robust method to prepare peptides in the laboratory as well as on an industrial scale.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide

Bartoloni¹,

Waltersperger²,

Bumann³

et al. 2014

Arkivoc

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(1b) was prepared and crystallized to assign its bridge stereochemistry. The bridge configuration appears as planned by the chirality of the branching amino acids. Bicyclization furthermore depends on the presence of matched chiralities in the branching amino acids. The stereoselective formation of the second bridge opens the way for the synthesis of a large family of bicyclic peptides as promising new scaffolds for drug design.

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“…Consequently, several other types of cyclic peptides, such as "homodetic side chain to side chain", "backbone to backbone", as well as a combinations of these have been described. [4] As part of one of our ongoing research programs devoted to the discovery of active depsipeptides-modeled on natural depsipeptides-a new concept of depsipeptide architecture has been designed. Cyclic depsipeptide dimers connected by a CC bond were constructed.…”

Section: Dedicated To Professor Klaus Burgermentioning

confidence: 99%

Siamese Depsipeptides: Constrained Bicyclic Architectures

Ruiz-Rodríguez¹,

Spengler²,

Alberício³

2009

Angewandte Chemie

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Die ersten Vertreter einer neuen Klasse von Depsipeptiden mit Weinsäure als zentraler Einheit – bezeichnet als siamesische Depsipeptide – wurden aus einer verzweigten Vorstufe in einem einzigen Cyclisierungsschritt erhalten. Strukturmodifikationen eines natürlichen bioaktiven Depsipeptids (Sansalvamid A) liefern Analoga mit höherer Aktivität und damit Zusatzinformationen über Struktur‐Aktivitäts‐Beziehungen (siehe Formeln).

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Synthesis of Bicyclic Peptides

Cited by 14 publications

References 42 publications

Peptide Bicycles that Inhibit the Grb2 SH2 Domain

Peptide Bicycles that Inhibit the Grb2 SH2 Domain

Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide

Siamese Depsipeptides: Constrained Bicyclic Architectures

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