Improving Precision Medicine: Dickinson Lab's Innovations with Covalent Macrocyclic Peptides
"Drugs that work by covalently labeling specific amino acid residues, particularly residues that cause the disease, are an exciting area of therapeutic development for diseases like cancer" explains Tong Lan, a graduate student with the Bryan Dickinson lab deeply engaged in research with covalent macrocyclic peptides.
Investigators like Lan are continuously seeking innovative approaches to target the complex mechanisms of cancer, aiming to develop treatments that are more effective and precise. A recent promising development in this area is the discovery and application of covalent macrocyclic peptides—an extraordinary class of compounds that are expanding the horizon of what medicinal chemistry can do.
Recently, a recent paper published in the Journal of the American Chemical Society by the Bryan Dickinson lab has presented a new approach to discover these molecules, offering a glimpse into a future where cancer treatment could become more targeted and effective than ever before.
Covalent macrocyclic peptides are not merely another addition to the pharmaceutical toolkit; they represent a significant advancement in scientists ability to target disease at a molecular level. These peptides are specifically designed to form irreversible bonds with target proteins, often critical players in disease pathways. This means that once they bind to a protein, they do so irreversibly, effectively tagging it for therapeutic intervention.
Lan, who is first author on the recently published study, emphasized the unique opportunity that covalent inhibitors provide in specifically targeting oncogenic mutations, such as the notorious KRAS G12C mutant.
"Covalent inhibitors allowed researchers to focus on these mutants instead of the wild-type KRAS protein, which is essential for many cellular activities," said Lan, noting this specificity is crucial in developing effective therapies that minimize off-target effects.
Traditional drug discovery has faced significant challenges developing small molecule drugs that can effectively bind to specific disease-related proteins. These small molecules take a lot of efforts to identify, and often resist efficient binding, leading to less effective treatments and unwanted side effects. This has prompted researchers like Lan to explore alternative approaches to overcome these limitations.
In her research, Lan recognized the shortcomings of small molecules and sought to design a new class of compounds that could offer greater specificity and potency and streamline the identification.
"I think the common sense is that the initial library design is very critical for success in terms of small molecule screening," said Lan.
She continued: “In our previous search, we were trying to identify more small molecule scaffolds to gather a small molecule library. We composed a library of thousands of compounds but none of those compounds showed any activity on our target protein.”
This struggle is not an isolated incident; many researchers have encountered similar difficulties when identifying effective small-molecule inhibitors to their target proteins.
As the Dickinson lab worked to create a library of covalent macrocyclic peptides, they aimed to screen against various disease-related proteins to identify those capable of irreversible binding. However, the path to discovery was not without its challenges.
Collaboration played a pivotal role in advancing their research. Lan worked closely with Professor Scott Snyder, an experienced organic chemist, to refine their methodologies. Their initial goal was to adapt a linker developed by Professor Matt Bogyo at Stanford University, for the mRNA display platform, but they soon discovered that the cyclic efficiency was not optimal.
"With the help of Professor Snyder, we were able to obtain a more reactive linker that improved our results significantly," says Lan.
The technical process involved integrating the mRNA display platform with linker to create covalent macrocyclic peptides library, optimizing the linker for effective binding, and ensuring that the library design was robust enough to yield meaningful results.
"We aimed to track every step of the process to ensure that we could generate covalent inhibitors for our target protein," she adds.
As the insights gained from Dickinson lab’s research not only deepen our understanding of the complexities and potential of covalent macrocyclic peptides, the future of cancer therapy may soon become increasingly targeted, offering new hope for patients facing this formidable disease.
“This research shows what covalently targeting proteins with macrocyclic peptides really offer,” said Lan, “which is a very unique opportunity for successful drug candidates.”
Citation - Tong Lan, Cheng Peng, Xiyuan Yao, Rachel Shu Ting Chan, Tongyao Wei, Anuchit Rupanya, Aleksandar Radakovic, Sijie Wang, Shiyu Chen, Scott Lovell, Scott A. Snyder, Matthew Bogyo, and Bryan C. Dickinson. Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display, Journal of the American Chemical Society 2024 146 (34), 24053-24060, DOI: 10.1021/jacs.4c07851