Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

Dengler, Sebastian; Mandal, Pradeep K.; Allmendinger, Lars; Douat, Céline; Huc, Ivan

doi:10.1039/d1sc03640h

Cited by 7 publications

(33 citation statements)

References 57 publications

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“…[15] Within the macrocycles, the folding propensity of the aromatic segments was shown to influence peptide conformation and enhance peptide resistance toward proteolytic degradation and, in a reciprocal effect, the chirality of the peptides was shown to bias foldamer helix handedness. [ 13 , 14 ]…”

Section: Resultsmentioning

confidence: 99%

“… [16] Typically, induced CD bands indicate handedness bias and a single set of signals on 1 H NMR spectra as well as a single HPLC peak confirm full handedness control. [13] The foldamer segment generally consisted of Q Asp and Q Dap charged residues to provide solubility in both basic and acidic aqueous media and was acetylated or acylated with a short diethylene‐glycol‐containing acid at the N‐terminus. A new Alloc‐protected Fmoc‐Q Dap(Alloc) ‐OH monomer was synthesized to anchor chloroacetamide functions at the final stage of solid phase synthesis.…”

Section: Resultsmentioning

confidence: 99%

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Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template

2022

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Hybrid sequences comprising a peptide with several Cys residues and an aromatic foldamer helix with several chloroacetamide functions at its surface were synthesized. Such products may in principle form numerous macromulticyclic thioether products by intramolecularly combining all Cys residues and all chloroacetamide functions. However, we show that the reactive sites on the structurally defined helix can be placed at such locations that the peptide selectively stitches itself to form a series of different macrocycles within mostly one preferred product. Reactions were monitored by HPLC and products with two, three or four macrocycles were identified using LC-MS and NMR. The series of selective macrocyclizations define a sort of reaction trail where reaction sites otherwise identical are involved successively because of their precise positioning in space. The trails can be predicted to a large extent based on structural considerations and the assumption that smaller macrocycles form faster.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template

2022

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“…Moreover, structures that are structurally distant from native miniproteins but also based on folding oligomeric molecules, have been also developed. These includes aromatic oligoamides or oligoureas that were shown to adopt miniprotein-like arrangements. , These new directions of research will extend and inevitably deliver new structures in the future.…”

Section: Discussionmentioning

confidence: 99%

Design and Engineering of Miniproteins

Ożga

Berlicki

2022

ACS Bio Med Chem Au

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The potential of miniproteins in the biological and chemical sciences is constantly increasing. Significant progress in the design methodologies has been achieved over the last 30 years. Early approaches based on propensities of individual amino acid residues to form individual secondary structures were subsequently improved by structural analyses using NMR spectroscopy and crystallography. Consequently, computational algorithms were developed, which are now highly successful in designing structures with accuracy often close to atomic range. Further perspectives include construction of miniproteins incorporating nonnative secondary structures derived from sequences with units other than α-amino acids. Noteworthy, miniproteins with extended structures, which are now feasibly accessible, are excellent scaffolds for construction of functional molecules.

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“…Händigkeit wird darüber hinaus durcheinzelne Signalsätze in 1 H NMR-Spektren sowie einzelne HPLC-Peaks bestätigen bewiesen. [13] Das Foldamer-Segment bestand im Allgemeinen aus geladenen Q Asp -und Q Dap -Resten, um die Löslichkeit sowohl in basischen, als auch in sauren wässrigen Umgebungen zu gewährleisten, und wurde am N-Terminus mit einer kurzen Diethylenglykol-haltigen Säure acetyliert oder acyliert. Ein neues Alloc-geschütztes Fmoc-Q Dap-(Alloc)À OH-Monomer wurde synthetisiert, um Chloracetamid-Funktionen in der letzten Synthesestufe der Festphase zu befestigen.…”

Section: Design Und Syntheseunclassified

“…Es hat sich gezeigt, dass die Faltungseigenschaften des aromatischen Segments innerhalb der Makrozyklen die Peptidkonformation beeinflussen und die Widerstandsfähigkeit des Peptids gegenüber proteolytischem Abbau erhöhen. Umgekehrt hat sich gezeigt, dass die Chiralität der Peptide die Händigkeit der Foldamer‐Helix beeinflusst [13, 14] …”

Section: Ergebnisse Und Diskussionunclassified

Differenzierte Peptid‐Multi‐Makrozyklisierungen an der Oberfläche eines helikalen Foldamer‐Templats

2022

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Es wurden hybride Sequenzen synthetisiert, die Peptide mit einer Reihe von Cystein-Resten und aromatische Foldamer-Helices mit mehreren Chloracetamid-Funktionen an ihrer Oberfläche umfassen. Solche Produkte können im Prinzip zahlreiche makromultizyklische Thioetherbrücken bilden, indem sie alle Cys-Reste und alle Chloracetamidfunktionen intramolekular verbinden. Wir zeigen indes, dass die reaktiven Stellen auf der strukturell definierten Helix an solchen Positionen platziert werden können, so dass das Peptid selektiv reagiert, um eine Reihe unterschiedlicher Makrozyklen innerhalb meist eines bevorzugten Produkts zu bilden. Die Reaktionen wurden mittels HPLC überprüft und die Produkte mit zwei, drei oder vier Makrozyklen wurden mittels LC-MS und NMR identifiziert. Die Reihe selektiver Makrozyklisierungen definiert eine Art Reaktionspfad, bei dem ansonsten identische Reaktionsstellen aufgrund ihrer genauen Positionierung im Raum nacheinander beteiligt sind. Die Reaktionspfade lassen sich weitgehend auf der Grundlage struktureller Überlegungen und der Annahme, dass sich kleinere Makrozyklen schneller bilden, vorhersagen.

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Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

Abstract: Macrocyclic peptides are an important class of bioactive substances. When inserting an aromatic foldamer segment in a macrocyclic peptide, the strong folding propensity of the former may influence the conformation...

Cited by 7 publications

References 57 publications

Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template

Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template

Design and Engineering of Miniproteins

Differenzierte Peptid‐Multi‐Makrozyklisierungen an der Oberfläche eines helikalen Foldamer‐Templats

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