Research
Cyclic Peptides
Synthetic methods
Permeability
Therapeutic applications
Targeting G1–S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors
Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A–E2F and cyclin B–MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B–CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.
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.
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
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
Form and Function of Cyclic Peptide Natural Products: A Pharmacokinetic Perspective
Cyclic peptide natural products adopt solvent-dependent conformations that permit passive permeability.
Discovery of Cell-Permeable Macrocyclic Cyclin A/B RxL Inhibitors that Demonstrate Antitumor Activity
Utilizing structure-based design, we have discovered a family of cell-permeable macrocyclic Cyclin A/B RxL inhibitors that show potent and selective activity against RB1/E2F-dysregulated cancer cell lines. Lead compound 34 demonstrated proof-of-concept efficacy via intraperiotoneal (IP) administration in mouse cell line-derived xenograft (CDX) tumor models.
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.
Beyond Cyclosporine A: Conformation-Dependent Passive Membrane Permeabilities of Cyclic Peptide Natural Products
Natural product permeability is rationalized via computational modeling
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
Structure-Permeability Relationships in Natural Product-Inspired Cyclic Peptides
PhD dissertation
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
Cucurbit[7]uril-Tetramethylrhodamine Conjugate for Direct Sensing and Cellular Imaging
A single-component sub-nanomolar optical sensor
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
