Cyclotide research looks for new drugs

Cyclotides are a unique group of plant proteins with unusual properties. Kalthera, a small Queensland biotech company, is developing technology to use them in therapeutic applications.

Professor David Craik, a scientist at the University of Queensland's Institute for Molecular Bioscience, said that cyclotide proteins were exceptionally stable and could even be boiled without being destroyed. The proteins are also resistant to enzymatic cleavage.

The reason behind this extraordinary stability is the protein's structure. Cyclotides are small cyclised proteins with several disulfide bonds creating a tightly knotted structure.

The first cyclotide protein, Kalata B1, was isolated from a small African plant called Oldenlandia affinis, and is the active ingredient in a uteroactive tonic given to women in labour. The molecule has since been shown to have insecticidal and antimicrobial properties, which suggests a role for the protein in the plant, which contains large quantities of Kalata B1 in most tissues.

Other cyclotides have been shown to have neurotensin and anti-HIV properties.

"There are no other proteins quite like them," said Craik, who is studying cyclotide proteins isolated from Australian and exotic plants.

"We presume they are in the plants as defense molecules."

Craik's group has found similar cyclotides in other plants, including many members of the Rubiaceae and Violaceae families. Altogether, Craik said, over 600 molecules had been identified in plant extracts. Peptide sequences of about 50 of these have been obtained, but only six genes have been identified to date.

His research has resulted in the determination of a consensus structure for the proteins. Craik and his team, in collaboration with Dr Marilyn Anderson from LaTrobe University, are studying the properties of these molecules as well as how they are produced and expressed.

In the meantime, Craik has formed Kalthera to explore the possibility of using the cyclotide structure to stabilise peptide therapeutics.

"We would like to take the stable framework and graft other biological activities onto it," said Craik. "There is room within the structure to insert small peptides.

"We are evaluating potential small peptide-based therapeutics that need to be made more stable. There should be general application to a wide range of peptide therapeutics."

Kalthera received a Biotechnology Innovation Fund grant last year to fund a proof of concept development program and also has funding from IMBcom - the commercial arm of the Institute.

"We are actively working on the commercial development of the program at the moment," Craik said.