One huge problem with developing drugs lies with protein behavior. Distorted proteins which cause disease can be very hard to reach from outside the cell, while protein-based drug candidates very often break apart, or can’t navigate intricate cell anatomy well enough to make a connection.
Pharmaceutical researchers have tried many ways to circumvent these problems; attaching a protein chain (known as a polypeptide) to a smaller molecule, attaching the peptides to a gene or virus that can enter the cell, or making complex peptide chains. While these approaches have had success, they haven’t eliminated important disease-causing proteins, which remain ‘undruggable.’ And the diseases are neither rare nor trivial; they include cancer, endocrine and metabolic disorders like diabetes, and inflammatory responses.
A new class of drugs that may finally contact these undruggables has been developed by a small Massachusetts biotech firm named Aileron Therapeutics. Called ‘stapled peptides,” they consist of two amino acids (the most basic building block of peptides/proteins) chemically ‘stapled’ together in a way that mimics the binding of more complex proteins. The difference is, unlike their bigger protein cousins, Aileron’s stapled peptides don’t fall apart. That makes them far more potent because they can deliver any payload to a protein target.
Aileron claims that this is the first new class of drugs to be tested in about 20 years. They also state that the platform took 25 years to develop (including some pretty groundbreaking genetic research that’s arisen in the field in general). The first drug to be developed from the platform, called ALRN-5281, will begin clinical trials soon, thanks to US$12 million that the company raised (and announced on Monday). The first trial, a phase one test, will determine the drug’s safety and effectiveness in a small group of participants. ALRN-5281 is designed to boost the release of human growth hormone in the body, thereby treating growth hormone deficiency and another endocrine disorder called HIV lipodystrophy. The company is looking at other stapled peptide candidates for cancers and metabolic diseases. If it works on growth hormone disorders, the new drug could replace the current therapeutic regime of injections, which don’t produce a steady stream of growth hormone in patients.
How does a stapled peptide work? A stapled peptide is one that has been chemically tweaked to maintain its unique shape (in this case, a conformation called the alpha-helix, which looks like a curly ribbon). Without that shape, it could be blasted apart by enzymes, and wouldn’t be as effective as a molecular switch. Too many protein-based drugs don’t retain that alpha-helix shape and don’t work. The stapled peptide retains its shape, and becomes biological stable, much more so that bigger proteins. It essentially merges the advantages of small molecules (evading the immune system, easily penetrating cell membranes and other defenses) with large biological molecules (acting more like ‘real’ biomolecules, more targeted treatments).
So, Aileron’s new drugs, if effective, could staple their way into a new way to evade cellular defenses and fight more diseases. They’re certainly causing a lot of chatter in the pharmaceutical industry!
Sheridan, C. (2010). Roche backs Aileron’s stapled peptides Nature Biotechnology, 28 (10), 992-993 DOI: 10.1038/nbt1010-992c