Peptide-based drug discovery has gained currency in the past decade. This branch of pharmaceuticals promises solutions to tricky health issues such as cancer. Now, two researchers from IIT-Bombay and one from the Technical University of Darmstadt, Germany, have reported work that suggests ways to improve peptide-based drug discovery.
Inside every living cell, thousands of proteins constantly interact with one another, switching genes on and off, repairing damage, carrying signals and deciding whether a cell should live or die. Many diseases, including cancer, arise when some of these protein–protein interactions go wrong.
One such interaction involves two proteins called p53 and MDM2. Normally these two proteins function together in a checks-and-balance manner. The p53 protein is a sort of sentinel — it triggers the destruction of cells that have gone bad, such as with cancer. Excess of p53 can be a problem. MDM2 comes in and suppresses p53. This is fine but sometimes p53 is less or MDM2 is more; when this happens, MDM2 prevents p53 — the guardian angel — from doing its job. Keeping track of such happenings in cells has given rise to the study of ‘protein-protein interaction’.
Precise stapling
Scientists have discovered that stapled peptides (see box) can bind themselves to MDM2 and prevent it from suppressing p53. This is because scientists have engineered the stapled peptides to resemble p53, and MDM2 attaches to them. This leaves p53 free to do its job, without hindrance from MDM2.
Drug discovery is about making the right kind of stapled peptide.
In a paper, the three researchers have used computer simulations to demonstrate that medical researchers should look not just at protein combinations but also the behaviour of the molecules in the solvent in which the proteins are immersed. In their study, the researchers focused on the behaviour of water molecules — the solvent — in the presence of stapled peptides.
Peptides are short chains of amino acids. In a sense, they are “dwarf proteins”.
Most people know proteins as body-building molecules — which is true — but there are thousands of different proteins. For example, snake venom is a cocktail of proteins, as is haemoglobin.
Both peptides and proteins are chains of amino acids. An amino acid is a molecule that has carbon, hydrogen, nitrogen, oxygen and a ‘side chain’ of molecules with other elements like sulphur. Since there are about 20 ‘side chains’, there are as many amino acids.
Stapled peptides are two peptides linked by a chemical. They are, therefore, engineered molecules.
They found that stapled peptides also altered the behaviour of water molecules. When a stapled peptide binds to its target protein, the water molecules gain ‘entropy’ or freedom, while the peptide itself becomes more stable and rigid. The behaviour of the water molecules could be manipulated to create more effective and ‘stickier’ medicines. Put simply, this means medicines (stapled peptides) can be made more effective by controlling how a drug interacts with the water molecules rather than by focusing only on the drug molecules’ shape and binding capability.
A more stable peptide binds better with its target — its efficacy increases. “Peptide-based drug discovery is an emerging field… Using in-silico (computer-based) approaches, effective peptide drug candidates can be identified and filtered at early stages. However, the detailed thermodynamics at the binding interface are often overlooked,” the researchers say in a joint statement to businessline.
They point out that in many ongoing drug discovery pipelines, the ‘entropic effects’ (freedom of movement of molecules) are largely ignored.
Therapeutic pathway
If a peptide’s binding property is improved, will it translate into a drug that requires lower doses or has fewer side effects?
“Stronger binding affinity can provide several practical advantages, including lower therapeutic doses, reduced off-target effects and potentially lower treatment costs. Importantly, understanding how stapling affects both peptide structure and surrounding water dynamics provides a… basis for the rational design of more effective peptide therapeutics,” the researchers respond in their statement.
However, they caution that translating the computational insights into clinical applications calls for more extensive experimental and clinical validation.
Interestingly, research into stapled peptides could well open the door to improved treatment for other diseases. “Researchers can identify optimal stapling positions and cross-linker chemistries that enhance binding affinity. This strategy expands opportunities for targeting challenging protein-protein interactions in areas such as oncology and immunology,” the statement says.
Published on June 1, 2026
