A new wave of designer molecules can infiltrate cells and block processes that cause diseases like cancer. These molecules are made of peptides, resembling short strings of pearls, where each pearl is an amino acid, the fundamental building blocks of proteins.
To transform these peptides into effective therapies, scientists can fashion them into specific shapes: a chemical ‘staple’ holds the peptide in a helical shape, much like using a paperclip to secure sheets of paper together.
“Stapled peptides are highly attractive molecules as they combine the capacity of antibodies to bind to target surfaces with high affinity, and potentially offer the ability of small molecules to permeate into cells,” explained Christopher J. Brown, a Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB).
Despite their promise, many stapled α-helical peptides either struggle to reach targets inside the cell or interact unintendedly with other molecules, leading to unreliable function or unwanted side effects in patients.
Collaborating with researchers from A*STAR’s Bioinformatics Institute (BII) and the Institute of Sustainability for Chemicals, Energy And Environment (ISCE2); as well as Uppsala University, Sweden, and industry partners Merck Sharp & Dohme (MSD), Brown investigated approaches for designing safe and effective stapled peptides.
In their study, the team created and tested over 350 variations of a specific peptide to assess how effectively they attach to their target, penetrate cells without harming cell membranes, and perform in various safety and efficacy tests. This stapled peptide was engineered to disrupt interactions between p53 and its regulator Mdm2, both key targets in cancer research.
The team found that by tweaking the amphipathic properties of peptides to balance their ‘water-loving’ and ‘water-hating’ interactions, they could improve the peptides’ ability to penetrate cells. The team also found that altering the peptides’ electrostatic charges reduced their toxicity.
“Another illuminating finding was how desirable properties of stapled peptides could be further improved via helical extensions,” remarked Brown. “Using longer, seven-amino-acid stapled peptide sequences with extended ends helped to improve their ability to enter cells and bind targets, as well as their solution properties and protection from breakdown.”
By applying these principles, they developed an approach that made the stapled peptides up to 292 times more effective at targeting and suppressing tumour growth in mice without affecting other cell functions.
“This insight very much enlarges the chemical space that can be used to optimise lead peptides and properties required for therapeutic candidates,” Brown commented.
In the next chapter of their work, the researchers are applying their iterative design process to more diverse targets and interfaces. They are also screening peptide libraries to discover more suitable starting templates for peptide design.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB), Bioinformatics Institute (BII) and the Institute of Sustainability for Chemicals, Energy And Environment (ISCE2).
