A Synthetic Loop Replacement Peptide That Blocks Canonical NF‐κB Signaling

Bruno, Paul A.; Morriss-Andrews, Alex; Henderson, Andrew; Brooks, Charles L.; Mapp, Anna K.

doi:10.1002/anie.201607990

Cited by 14 publications

(9 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[127,128] However,m ost efforts continue to focus on stapled a-helices.I tw ill be an important development in the next few years if other secondary structures,s uch as beta-hairpins or even nonnatural foldamers,c an be tailored with amphipathic patterning to enable similar mechanisms of entry as stapled ahelices. [129,130]…”

Section: Amphipathic Patterning Canp Romote Endocytic Uptake For Consmentioning

confidence: 99%

Emerging Methods and Design Principles for Cell‐Penetrant Peptides

2018

View full text Add to dashboard Cite

Biomolecules such as antibodies, proteins, and peptides are important tools for chemical biology and leads for drug development. They have been used to inhibit a variety of extracellular proteins, but accessing intracellular proteins has been much more challenging. In this review, we discuss diverse chemical approaches that have yielded cell-penetrant peptides and identify three distinct strategies: masking backbone amides, guanidinium group patterning, and amphipathic patterning. We summarize a growing number of large data sets, which are starting to reveal more specific design guidelines for each strategy. We also discuss advantages and disadvantages of current methods for quantifying cell penetration. Finally, we provide an overview of best-odds approaches for applying these new methods and design principles to optimize cytosolic penetration for a given bioactive peptide.

show abstract

Section: Amphipathic Patterning Canp Romote Endocytic Uptake For Consmentioning

confidence: 99%

Emerging Methods and Design Principles for Cell‐Penetrant Peptides

2018

View full text Add to dashboard Cite

show abstract

“…Der gleiche Befund wurde auch fürv iele andere geklammerte Helices ermittelt. [129,130] 3. [120] Ebenso fanden Grossmann und Mitarbeiter,dass bei doppelt geklammerten Rab8a-Antagonisten Substitutionen nçtig waren, um die negative Ladung zu verringern und die Hydrophobie zu erhçhen und so die Zellaufnahme und Aktivität in Zellkultur zu verbessern.…”

Section: Maskierung Von Rückgratamiden Kann Kleine Cyclischeunclassified

“…Eine wichtige Entwicklung der nächsten Jahre wird sein, andere Sekundärstrukturen, wie Beta-Haarnadelkurven oder sogar nicht-natürliche Foldamere,m it maßgeschneiderter amphipathischer Strukturierung herzustellen, die ähnlichen Aufnahmemechanismen wie geklammerte a-Helices folgen. [129,130]…”

Section: Die Strukturierung Von Guanidingruppen Kann Die Endozytischeunclassified

Neue Methoden und Designprinzipien für zellgängige Peptide

Peraro

Kritzer

2018

Angewandte Chemie

View full text Add to dashboard Cite

Biomoleküle, wie Antikörper, Proteine und Peptide, sind wichtige Werkzeuge in der chemischen Biologie und Ansatzpunkte für die Wirkstoffentwicklung. Sie wurden erfolgreich verwendet, um eine Reihe von extrazellulären Proteinen zu inhibieren, allerdings stellt die Interaktion mit intrazellulären Proteinen eine weit größere Herausforderung dar. In dieser Aufsatz diskutieren wir unterschiedliche chemische Ansätze, die zu zellgängigen Peptiden geführt haben, und identifizieren drei eigenständige Vorgehensweisen: die Maskierung von Rückgratamiden, die Strukturierung von Guanidingruppen und die amphipathische Strukturierung. Wir fassen zusammen, wie anhand großer Datensätze, die in steigendem Maße entstehen, spezifischere Designprinzipien für jede dieser Strategien abgeleitet werden können. Wir beschreiben außerdem Vor‐ und Nachteile gängiger Methoden zur Quantifizierung der Zellpenetration. Abschließend geben wir eine Übersicht über die vielversprechendsten Ansätze für die Anwendung dieser neuen Methoden und Designprinzipien zur Optimierung der zytosolischen Penetration eines bioaktiven Peptids.

show abstract

“…However, its low potency and poor pharmacokinetics (e.g., serum half-life of ~15 min) prevented further clinical development. We 38 and others 39 have attempted to improve the potency, proteolytic stability, and/or cell-permeability of Antp-NBD through cyclization, but the potency of the resulting peptides remained rather modest (IC 50 in the low μ M range). In this work, we have discovered a relatively potent bicyclic peptidyl inhibitor against the NEMO-IKK interaction (IC 50 =1.0 μ M), by screening of a combinatorial library followed by limited optimization.…”

Section: Introductionmentioning

confidence: 99%

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library

et al. 2018

View full text Add to dashboard Cite

Macrocyclic peptides are capable of binding to flat protein surfaces such as the interfaces of protein–protein interactions with antibody-like affinity and specificity, but generally lack cell permeability in order to access intracellular targets. In this work, we designed and synthesized a large combinatorial library of cell-permeable bicyclic peptides, in which the first ring consisted of randomized peptide sequences for potential binding to a target of interest, while the second ring featured a family of different cell-penetrating motifs, for both cell penetration and target binding. The library was screened against the IκB kinase α/β (IKKα/β)-binding domain of NF-κB essential modulator (NEMO), resulting in the discovery of several cell-permeable bicyclic peptides, which inhibited the NEMO-IKKβ interaction with low μM IC50 values. Further optimization of one of the hits led to a relatively potent and cell-permeable NEMO inhibitor (IC50 = 1.0 μM), which selectively inhibited canonical NF-κB signaling in mammalian cells and the proliferation of cisplatin-resistant ovarian cancer cells. The inhibitor provides a useful tool for investigating the biological functions of NEMO/NF-κB and a potential lead for further development of a novel class of anti-inflammatory and anticancer drugs.

show abstract

A Synthetic Loop Replacement Peptide That Blocks Canonical NF‐κB Signaling

Cited by 14 publications

References 46 publications

Emerging Methods and Design Principles for Cell‐Penetrant Peptides

Emerging Methods and Design Principles for Cell‐Penetrant Peptides

Neue Methoden und Designprinzipien für zellgängige Peptide

Cell-Permeable Bicyclic Peptidyl Inhibitors against NEMO-IκB Kinase Interaction Directly from a Combinatorial Library

Contact Info

Product

Resources

About