Brown CJ
Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein
DAXX (Death Domain Associated Protein 6), initially identified as a potentiator of apoptosis, is known to play crucial roles in several vital biological pathways, including chromatin remodeling, transcription regulation, DNA repair, and innate immunity. Its increased expression has been observed in diverse, epidemiologically prevalent cancers
ReadA high-throughput microfluidic mechanoporation platform to enable intracellular delivery of cyclic peptides in cell-based assays
Cyclic peptides are poised to target historically difficult to drug intracellular protein–protein interactions, however, their general cell impermeability poses a challenge for characterizing function.
ReadEngineering an Autonomous VH Domain to modulate intracellular pathways and to Interrogate the eIF4F Complex
Approaches have been devised to increase the discovery rate of intrabodies but often these yield results that aren’t functional in cells. Here the authors engineer and optimise an autonomous and disulphide-free human VH domain for intracellular expression, and they identify several VH domain binders against eIF4E.
ReadConformational ordering of intrinsically disordered peptides for targeting translation initiation
Intrinsically disordered regions (IDRs) in proteins can regulate their activity by facilitating protein-protein interactions (PPIs) as exemplified in the recruitment of the eukaryotic translation initiation factor 4E (eIF4E) protein by the protein eIF4G. Deregulation of this PPI module is central to a broad spectrum of cancer related malignancies and its targeted inhibition through bioactive peptides is a promising strategy for therapeutic intervention.
ReadDe-risking drug discovery of intracellular targeting peptides: screening strategies to eliminate false-positive hits
Non-specific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here, we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1A and cyclorasin 9A5, exemplify false-positive molecules – both in terms of their binding affinities and cellular activities.
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.
ReadStructural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein
Stapled-peptides have emerged as an exciting class of molecules which can modulate protein–protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein.
ReadMacrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges
Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials.
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