Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix

Smith, Jessica M.; Frost, John R.; Fasan, Rudi

doi:10.1039/c4cc01199f

Cited by 33 publications

(36 citation statements)

References 39 publications

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“…[3, 4] Numerous peptide therapeutics have been developed to target this interaction, with some reaching as far as early-phase clinical trials. [5–10]…”

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confidence: 99%

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

et al. 2015

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Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein-protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide-alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. α-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications.

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“…[3, 4] Numerous peptide therapeutics have been developed to target this interaction, with some reaching as far as early-phase clinical trials. [5–10]…”

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confidence: 99%

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

et al. 2015

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“…[113] Peptidpolyketide bilden eine weitere wichtige Klasse,die von natürlichen Strukturen abgeleitet wurde,u nd umfassen Chondramid, Jaspakinolid und Seragamid, die an Aktin binden und dessen Polymerisation beeinflussen. [116] Ein a-Helixbindungsmotiv aus zehn Aminosäuren wurde durch Phagendisplay identifiziert und anschließend mithilfe eines aromatischen Oxim-Linkers vom Kopf zur Seitenkette cyclisiert. Zum Beispiel wurden neue Analoga von Largazol, einer aus marinen Cyanobakterien isolierten Vorstufe eines hybriden, cyclischen Peptidhiston-Deacetylase(HDAC)-Inhibitors,e ntwickelt, indem die ursprüngliche Thiazoleinheit durch verschiedene Pyridinderivate ersetzt wurde (Abbildung 7b).…”

Section: Hybride Peptid-makrocyclenunclassified

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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“…9,30–33 More recently, complementary methodologies has been developed to enable the biosynthesis of cyclic and bicyclic peptides of arbitrary sequence in living bacterial cells. 34–36 As illustrated in these and other studies, 18,37 the type of backbone connectivity and intramolecular linkage can play a significant role in affecting the functional properties (e.g., protein binding affinity) of the resulting macrocyclic peptide.…”

Section: Introductionmentioning

confidence: 99%

Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids

Frost

Lam

et al. 2016

Org. Biomol. Chem.

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A strategy for the production of side-chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Two genetically encodable unnatural amino acids, bearing either an aryl or alkyl amino group, were investigated for their efficiency toward promoting the formation of medium to large-sized peptide macrocycles via intein-mediated side-chain-to-C-terminus cyclization. While only partial cyclization was observed with precursor proteins containing para-amino-phenylalanine, efficient peptide macrocyclization could be achieved using O-2-aminoethyl-tyrosine as the reactive moiety. Conveniently, the latter was generated upon quantitative, post-translational reduction of the azido-containing counterpart, O-2-azidoethyl-tyrosine, directly in E. coli cells. This methodology could be successfully applied for the production of a 12mer cyclic peptide with enhanced binding affinity for the model target protein streptavidin as compared to the acyclic counterpart (KD: 5.1 μM vs. 22.4 μM), thus demonstrating its utility toward the creation and investigation of novel, functional macrocyclic peptides.

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Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix

Cited by 33 publications

References 39 publications

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

Double Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids

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