Crypteins: Hidden Gems

When liberated, certain peptides within proteins exhibit surprising biological activities. Proteolytic cleavage reveals these concealed peptides and enables them to exert their biological effects. Nature uses this route to get the most out of a limited number of genome-encoded proteins, but Cryptome Pharmaceuticals, Melbourne, Australia, has other plans: It hopes to mine these hidden gems, which the company has nicknamed "crypteins," for potential therapeutics.

Protein chemist and cofounder A. Ian Smith of Monash University, in Melbourne, explained his company's approach at Pacifichem 2005, in Honolulu.

Crypteins play a key regulatory role in many biological processes, including angiogenesis, immune function, and cell growth, but their biological activity often cannot be predicted from that of their parent protein. More than a dozen of these peptides are being investigated as potential therapeutics, including the 38-kilodalton plasminogen fragment angiostatin for cancer treatment and the three-amino-acid insulin-like growth factor fragment glypromate for neuroprotection.

Thus far, crypteins have been identified by serendipity or through exhaustive searches of biological fluids or tissue extracts, Smith noted. Because such procedures are tedious and may not reveal low-abundance bioactive peptides, "it's likely that a huge number of crypteins involved in regulating disease processes have yet to be discovered," he told C&EN. His company is using proteolytic enzymes to systematically fragment isolated proteins or protein mixtures in vitro, he explained. The resulting cryptein libraries are then screened for various biological activities.

For instance, the company has screened cryptein libraries from blood for peptide fragments that prevent blood clotting. Smith said the company hopes soon to begin human testing of one particularly promising peptide, a 39-amino-acid fragment of a protein subunit of high-density lipoprotein that had never been associated with anticoagulation. More recently, the firm has started hunting for crypteins from milk proteins that might block cancer proliferation and inflammation, he added.

Smith is confident that his company eventually will be able to circumvent the manufacturing and delivery problems that continue to bedevil makers of protein-based therapeutics. "We hope to find the minimum peptide that retains biological activity and use it as a template to make nonpeptide cryptein analogs," he said in an interview.