THE DISCOVERY OF STAPLED PEPTIDES

Aileron is founded on the science of preeminent and renowned researchers Gregory L. Verdine, PhD, a Harvard University chemical biologist and pioneer of numerous chemical modalities, including the Stapled Peptide; Stanley J. Korsmeyer, MD, the late Professor of Pathology and Molecular Oncology at Harvard Medical School and Dana-Farber Cancer Institute and one of the principal discoverers of the oncogene Bcl-2 and its homologues; and Loren D. Walensky, MD, PhD, Dana-Farber, Children’s Hospital Boston and Harvard Medical School pediatric oncologist and cancer chemical biologist.

The groundbreaking work from these scientists -- the revolutionary designs and chemical constructs from Verdine, the breakthrough understandings in biology from Korsmeyer and the ultimate integration and transformation of the chemistry and biology into clinical application from Walensky are the foundation of Aileron’s Stapled Peptide Therapeutics, which represent a completely new therapeutic modality.

The earliest work on Stapled Peptides began in the mid-1990s, when Dr. Verdine sought to unlock the power of peptides through developing chemically-stabilized alpha-helical peptides with his colleague Christian Schafmeister. Together, Verdine and Schafmeister successfully designed a revolutionary hydrocarbon staple that ‘locked’ a flexible peptide into the shape of an alpha-helix, mimicking the form found in nature. As a result of stabilizing the helical structure, the novel Stapled Peptide was capable of resisting protease activity, which is critical as proteases rapidly degrade peptides in the body, eliminating or reducing their therapeutic potential. (J. Am. Chem. Soc. 2000, 122, 5891).

Simultaneously, Dr. Korsmeyer, who discovered the Bcl-2 oncogene, sought to develop a bridge between his laboratory’s breakthrough biology and the development of chemical tools, or actual drugs, to effectively target and silence these oncogenes.

To further pursue these efforts, Korsmeyer recruited Dr. Walensky, who joined Dana-Farber as its first chemical biologist. Walensky’s goal was to develop a new chemical entity that could effectively target Bcl-2 family proteins, and the first project evaluated the protein called “BID,” which has a short, coiled segment, a helical peptide, that is capable of triggering apoptosis, or programmed cell death. However, when helical domains are produced in the laboratory as discrete entities disconnected from the entire protein, they lose their shape. This decreases their biological activity and renders them susceptible to degradation by proteases and prevents the cellular uptake necessary to exert their biological activity.

To mine the promise of the BID protein and further investigate potential chemical solutions, Korsmeyer and Walensky began a groundbreaking collaboration with Verdine to apply his pioneering research in the field of chemically-stabilized peptides to biological applications for targeting Bcl-2 family proteins; from this landmark collaboration came the seminal discovery of the first biologically active Stapled Peptide.

Working in both the Korsmeyer and Verdine laboratories, Walensky constructed a tiny “staple” from non-natural amino acids to reinforce the native apoptosis-inducing BH3 helix from BID. Hydrocarbon stapling of the BID-BH3 peptide restored its natural structure, dramatically enhanced its biological activity and most remarkably, enabled the apoptosis-inducing helix to penetrate intact cells.

In a seminal preclinical study, the stapled BID-BH3 peptide entered leukemia cells, targeted Bcl-2 family proteins and triggered apoptosis. (Science 2004, 305, 1466). Strikingly, when the stabilized peptides were tested in a preclinical animal model of refractory pediatric leukemia, the disease was suppressed.