Peptides are a proven drug class, with more than 40 marketed therapeutics and approximately 300 agents in clinical trials. But despite the importance of peptide drugs, their therapeutic potential has historically been limited by poor pharmacokinetic properties resulting from in vivo proteolysis and poor cellular penetration, making it difficult for peptides to reach intracellular targets. Our proprietary cell-permeating peptide platform enables us to chemically stabilize and improve the performance and activity of a broad range of peptides that may provide therapeutic benefit in oncology and other diseases.
Our platform is designed to generate drug-like peptides that mimic the specific helical structures found at the interface of protein -protein interactions. These helical peptide domains act as nature’s locks and keys and enable two proteins to interact to control cellular function. More than 3000 intracellular protein-protein interactions are facilitated by such helical peptides, and many of these protein-protein interactions involve signaling cascades such as HIF1-α, Bcl-2 or p53 that are vital to malignant transformation and cancer cell proliferation.
We stabilize peptides by synthetically manufacturing and “stapling” them with hydrocarbon bonds into their natural alpha-helical conformation. We achieve this by inserting into the peptides two or more non-natural amino acids that, when catalyzed by a chemical reaction, form a bridge to lock the peptides into a helix and maintain the biological activity of the peptide. The stabilized helical structure of our peptides creates cell-permeating therapeutic agents with large molecular surfaces for optimal target binding properties, resulting in unique drugs like ALRN-6924
We believe our platform solves many of the inherent limitations of peptides and enables us to pursue high value targets that are undruggable by existing drug technologies. Although there have been several published examples of other peptide stabilization strategies, they have not translated into clinically relevant drugs for intracellular targets. Our all-hydrocarbon staple, or linker, has emerged as a solution that improves protease resistance, enables cellular penetrance and maintains biological activity. And because our cell-permeable peptides are larger in size than typical small molecule drugs, they can better interface with the broad, shallow binding pockets of these critical intracellular protein-protein interactions.
Peptides are functional subunits of proteins that act as nature’s locks and keys and enable two proteins to interact to control cellular function.
The alpha-helical structure is the most common peptide structure found at these protein interfaces.
Because peptides lose their shape by unwinding when removed from their natural protein scaffold, their chemical stability and activity is greatly reduced.
At Aileron, we stabilize peptides by “stapling” them with hydrocarbon bonds into their natural alpha-helical conformation.
Unlike large proteins, such as monoclonal antibodies or other naturally occurring proteins, that do not penetrate cell membranes due to their size and biophysical properties, stabilized alpha-helical peptides can in many circumstances penetrate cells and still maintain high affinity to their large protein surface targets. Our cell-permeating peptides typically retain the molecular target specificity of their underlying native protein structure.
Over 3,000 known protein-protein interactions are mediated by a helical peptide interface; our data and a growing body of third-party publications support the utility of cell-permeating peptides against a wide variety of targets.
We believe that our cell-permeating peptide chemical strategy may allow us to improve on many of the intrinsic limitations of peptides and to develop molecules that interact with high value targets that may not be amenable to small molecules or monoclonal antibodies.