Cell‐Permeable Peptides Containing Cycloalanine Residues

Wu, Hao; Mousseau, Guillaume; Mediouni, Sonia; Valente, Susana T.; Kodadek, Thomas

doi:10.1002/ange.201605745

Cited by 10 publications

(2 citation statements)

References 31 publications

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“…Depsipeptide linkages are found in some bioavailable natural products: for instance, anthelmintic PF1022A cyclic octapeptide features four ester bonds, 110 and antibiotic cyclic hexapeptide beauvericin has three esters and three N-methyl amides, 111 effectively leaving it with no HBDs. Other approaches toward reducing the number of HBDs include the use of N-alkylated peptoids and peptoid-peptide hybrids, as described in a recent study where authors incorporated cycloalanine residues to create a cell-permeable variant of HIV Rev protein-binding peptide, 112 and the use of oxa-and thiazole moieties, which are heavily featured in both RiPPs and NRPs (Figure 4). It should be noted, however, that because passive diffusion of peptides disfavors excessive HBDs and HBAs, many orally available peptides display predominantly hydrophobic amino acid side chains (Leu, Ile, Val, Trp, Phe, etc.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

2019

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Peptides as a therapeutic modality attract much attention due to their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered “undruggable”. Unfortunately, at the same time, other pharmacological properties of a generic peptide, such as metabolic stability and cell permeability, are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here, we review how macrocyclization as well as the incorporation of nonproteogenic amino acids and various conjugation strategies may be utilized to improve on these characteristics to create better drug candidates. We analyze recent progress and remaining challenges in improving individual pharmacological properties of bioactive peptides, and offer our opinion on interfacing these, often conflicting, considerations, to create balanced drug candidates as a potential way to make further progress in this area.

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Section: Journal Of the American Chemical Societymentioning

confidence: 99%

Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

2019

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“…263 To avoid the synthetic challenges associated with N αmethylated residues, Kodadek and colleagues employed cycloalanine residues to eliminate backbone amides, as well as introduce conformational rigidity, producing passively diffusible cyclic peptides with promising proof-of-concept biological activity. 264 As reported by Rezai et al, varying the side-chain stereochemistry provides another avenue to optimize backbone geometry of a model cyclic peptide, with one scaffold demonstrating permeability rivaling that of CsA. 95 Fouchéet al recently reported larger passively diffusible macrocycles of similar size to CsA, as opposed to prototypic macrocyclic scaffolds of ∼5−7 residues.…”

Section: Application Of Mechanisticmentioning

confidence: 99%

Understanding Cell Penetration of Cyclic Peptides

2019

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Approximately 75% of all disease-relevant human proteins, including those involved in intracellular protein−protein interactions (PPIs), are undruggable with the current drug modalities (i.e., small molecules and biologics). Macrocyclic peptides provide a potential solution to these undruggable targets because their larger sizes (relative to conventional small molecules) endow them the capability of binding to flat PPI interfaces with antibody-like affinity and specificity. Powerful combinatorial library technologies have been developed to routinely identify cyclic peptides as potent, specific inhibitors against proteins including PPI targets. However, with the exception of a very small set of sequences, the vast majority of cyclic peptides are impermeable to the cell membrane, preventing their application against intracellular targets. This Review examines common structural features that render most cyclic peptides membrane impermeable, as well as the unique features that allow the minority of sequences to enter the cell interior by passive diffusion, endocytosis/endosomal escape, or other mechanisms. We also present the current state of knowledge about the molecular mechanisms of cell penetration, the various strategies for designing cell-permeable, biologically active cyclic peptides against intracellular targets, and the assay methods available to quantify their cell-permeability.

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Neue Methoden und Designprinzipien für zellgängige Peptide

Peraro

Kritzer

2018

Angewandte Chemie

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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.

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Cell‐Permeable Peptides Containing Cycloalanine Residues

Cited by 10 publications

References 31 publications

Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges

Understanding Cell Penetration of Cyclic Peptides

Neue Methoden und Designprinzipien für zellgängige Peptide

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