Partridge AW
De-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.
ReadThe dual interactions of p53 with MDM2 and p300: Implications for the design of MDM2 Inhibitors
Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2.
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.
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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