Categories: ACS Spring 2014 |  Comments
How childbirth in rural Africa, petunias and deadly marine snails combined to open the door for new types of drug.
In the future, sufferers of chronic pain may simply need to sip petunia tea or pop a petunia seed pill in order to alleviate their symptoms. These petunias would have been genetically modified to produce small, circular peptides very similar to conotoxins, produced in the wild by a family of marine molluscs called cone snails.
Conotoxins have been investigated as potential painkillers for at least a decade. As slow moving animals, cone snails rely on a cocktail of chemicals that rapidly targets the nervous system to paralyse their prey before they can eat them. One drug based on these toxins, ziconotide (Prialt), is already approved for use in humans, but this protein drug is broken down in the digestive tract so it must be administered into the spine. Although effective, this method is intrusive and creates an infection risk, so is understandably undesirable.
David Craik and his team at the University of Queensland realised that they could make an oral version of these peptides by cyclisation – using solid-phase peptide chemistry to link the two end amino acids into a closed loop. Through this process they have manufactured a number of peptides that block chronic pain in rodent models more effectively than morphine and gabapentin, the current gold standard for chronic pain.
At the American Chemical Society meeting in Dallas, Texas, Craik announced the design and development of five new synthetic cyclic peptides based on the cone snail toxins. Importantly, they have also identified examples of plants within five major families that naturally produce cyclic peptides: rubiacae (including coffee), violaceae (violets and pansies), cucurbitaceae (squashes, cucumbers, watermelons and more), solanaceae (such as potato and tomato) and fabaceae (legumes).
Craik now hopes to incorporate genes for their designed peptides into plants, and has identified the petunia as a very good host. ‘When we started to do this work, we originally thought that we would use tobacco as the host plant: it’s a very easy plant to transform and it’s a model plant. When we put the genes for related molecules into tobacco, we did produce some cyclic peptide, but we got mainly linear. That’s where the petunia is the big breakthrough. Petunia already produces cyclotides, and so if we put a foreign modified conotoxin gene into it, the petunia is fantastic at producing the cyclic version with almost no misprocessed linear version.’ This opens the door for new cyclic peptide based drugs that are able to be used for more than just pain control, and as these drugs can be very well targeted, they could reduce the burden of side effects.
The plant-based method also allows drugs to be developed away from the sterile laboratory environment, according to Craik: ‘We started this work thinking that we could actually make medicine for third world countries. Not so much pain drugs, but for other applications. The reason we got on to circular plant proteins in the first place was because women in Africa take a plant, called Oldenlandia affinis, make a tea from it, sip the tea during labour and it accelerates childbirth. It turns out that the active uterotonic agent is a cyclic peptide called kalata-B1. … We were thinking that if we could put high tech protein drugs into plants like that in Africa then people could have these sorts of medicines essentially growing in their back yard.’