Macrocyclic peptides: a new research frontier
By combining the potency and targeting power of a biologic with the ease of administration of a pill, macrocyclic peptides have the potential to lead to new ways to impact patient care
September 18, 2025
But it’s challenging for small molecules to impact the large featureless surfaces of protein-protein interactions, which govern a wide range of biological processes in our bodies.
To target these interactions, scientists have turned to large molecule biologic therapies, like monoclonal antibodies, which — taken by infusion or injection — have been critical in advancing the treatment of many diseases, including some cancers and autoimmune disorders.
Over a decade ago, MSD scientists began investigating a way to create a new kind of medicine that would combine the potency and precise targeting of an antibody with the stability and ease of administration of a small molecule or pill.
“Macrocyclic peptides allow us to cast a wider net on the protein interactions we want to drug, providing a vast and untapped opportunity to access a wider range of targets and potentially new ways to treat different diseases,” said Dani Schultz, director of chemistry.
An intermediate-sized modality: not too big, not too small
Macrocyclic peptides, with their intermediate size — not too big, not too small — combine the properties of both small molecules and biologics. With their larger size and unique ring shape, macrocyclic peptides can tightly bind ample surface area to disrupt protein-protein interactions compared to traditional, linear-shaped peptide therapies.
“The design and invention of macrocyclic peptides is notoriously complicated,” said David Thaisrivongs, director of chemistry.
“Similarly, scaling production up for a macrocyclic peptide small molecule, with four to five times the size and complexity of a typical small molecule, represented a bold endeavor.”
- David Thaisrivongs
Director of chemistry, MSD
For our researchers, this work started by screening large libraries of cyclic peptides using messenger RNA display technology. This led to the identification of cyclic peptide leads that were optimized using 3-dimensional protein structure-based design and advanced computational techniques. Further molecular iterations and refinements improved the absorption, potency and stability of the first candidate.
“A diverse, interdisciplinary team of skilled and determined people from across our chemistry organization has dedicated substantial efforts to advancing this science,” said Thaisrivongs.
Macrocyclic peptides potentially open new possibilities in drug discovery
Our ongoing macrocyclic peptide discovery efforts represent a new era in drug discovery which may one day allow us to treat diseases that have long evaded traditional small molecule approaches and help improve access to medicines typically administered via injection or intravenously.
“Macrocyclic peptides are a new modality, and we’re still in the early stages of understanding their potential to impact disease and patient care,” said Schultz.
“There’s no playbook here, we’re innovating and developing new techniques on how to optimize and synthesize macrocyclic peptides — it’s really thrilling for me as a scientist because the potential is huge.”
- Dani Schultz
Director of chemistry, MSD
