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Research

Cyclic Peptides

Synthetic methods

Permeability

Therapeutic applications

Abstract 1560: Orally bioavailable macrocycles that target cyclins A and B RxL motifs cause tumor regression in xenograft models and in vitro show activity across multiple cancer types

Using structure-guided design we have developed cell-permeable macrocycle compounds that inhibit the RxL-mediated binding of substrates to both Cyclin A/CDK2 and Cyclin B/CDK1 complexes (Cyclin A/B RxL inhibitors) and have demonstrated that synthetic lethality requires inhibition of both Cyclins A and B

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Cyclic Peptide Natural Products Chart the Frontier of Oral Bioavailability in the Pursuit of Undruggable Targets

Cyclic peptides are potentially the future of intracellular protein-protein interaction inhibition. We review intrinsically permeable cyclic peptide therapeutics and model systems. 

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Beyond Cyclosporine A: Conformation-Dependent Passive Membrane Permeabilities of Cyclic Peptide Natural Products

Natural product permeability is rationalized via computational modeling

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Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products

Non-proteinogenic backbone elements permit passive permeability and oral bioavailability

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Structure-Permeability Relationships in Natural Product-Inspired Cyclic Peptides

PhD dissertation

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Cyclative Release of Peptidic Compounds

The present disclosure provides efficient and reliable methods for preparing cyclized peptidic compounds. Advantageously, the currently described methods allow for on-resin cyclization using a limited number of processing steps, while increasing the chemical diversity available for the cyclized peptidic compounds produced.

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Chapter 5: Bioactive and Membrane-Permeable Cyclic Peptide Natural Products

A summary of structure-permeability lessons and a survey of the diverse structures observed in bioactive cyclic peptide natural products

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Going Out on a Limb: Delineating the Effects of β-branching, N-Methylation, and Side Chain Size on the Permeability, Solubility, and Flexibility of Sanguinamide A Analogs

Lipophilicity and flexibility play important roles in determining the passive permeability of a cyclic peptide natural product

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Form and Function of Cyclic Peptide Natural Products: A Pharmacokinetic Perspective

Cyclic peptide natural products adopt solvent-dependent conformations that permit passive permeability.

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Synthetic Receptors

Cucurbiturils

Molecular recognition of peptides and proteins

Aromatic interactions

Molecular Recognition of Methionine-Terminated Peptides by Cucurbit[8]uril

Cucurbit[8]uril recognizes methionine-aliphatic side chain pairs with high affinity. No aromatic residue required!

Predictive Recognition of Native Proteins by Cucurbit[7]uril in a Complex Mixture

Selective recognition of proteins with N-terminal Phe residues using a resin-based tool

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Cucurbit[7]uril-Tetramethylrhodamine Conjugate for Direct Sensing and Cellular Imaging

A single-component sub-nanomolar optical sensor

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Chapter 6: Molecular Recognition of Aromatic Peptides and Proteins in Nature and by Design

The unique properties of aromatic residues afford strong and selective interactions with proteins and synthetic receptors

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