Tan YS
Cyclisation strategies for stabilising peptides with irregular conformations
Cyclisation is a common synthetic strategy for enhancing the therapeutic potential of peptide-based molecules. While there are extensive studies on peptide cyclisation for reinforcing regular secondary structures such as α-helices and β-sheets, there are remarkably few reports of cyclising peptides which adopt irregular conformations in their bioactive target-bound state.
ReadStraightforward incorporation of multiple ligand types into molecular dynamics simulations for efficient binding site detection and characterization
Binding site identification and characterization is an important initial step in structure-based drug design. To account for the effects of protein flexibility and solvation, several cosolvent molecular dynamics (MD) simulation methods that incorporate small organic molecules into the protein's solvent box to probe for binding sites have been developed.
ReadIncorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties
Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus.
ReadTargeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides
Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53-MDM2 protein-protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53-MDM2 PPI.
ReadStereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles
All-hydrocarbon, i, i+7 stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis via olefin metathesis results in the formation of both E- and Z-isomers, an observation that is rarely disclosed but may be of importance in targeting PPI.
ReadEfficient development of stable and highly functionalised peptides targeting the CK2a/CK2b protein–protein interaction
The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics.
ReadInhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides
S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis.
ReadRoles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting
The multi-faceted role of the transcription factor p53 is key to numerous biological processes, including the suppression of tumours. The availability since the 1990s of a richness of biophysical data aimed at understanding its structure-function relationships has enabled the application of a variety of atomistic computational modelling techniques towards the establishment of mechanistic models.
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