A deadly solution

As Big Pharma struggles to find the next blockbuster drug, could nature have some clues? One company thinks so – and they think the key lay in some of the world’s most deadly animals

Drug discovery companies are in the business of looking for the next blockbuster drug – but finding it can be incredibly difficult.

Many drugs have been discovered by identifying an active ingredient from a traditional remedy, or completely accidentally. In the 1990s, Big pharma companies switched their focus from natural products to combinatorial chemistry to deliver potential therapeutic compounds because of the lower costs and clarity on intellectual property – and because it could supply huge synthetic libraries in a short space of time.

Natural products were side-lined because identification, isolation and purification couldn’t keep up with high throughput screening, and the process was slow, inefficient and difficult.

http://www.youtube.com/watch?v=T6KuAXhnly4

The combinatorial chemistry approach involves the rapid synthesis or computational simulation of large numbers of molecules that may be useful drug candidates. The result is a library of different but related compounds that show little difference in their properties, making it difficult to decide with confidence what compounds to prioritise for testing.

Not only that, the traditional process of designing, synthesising, testing and redesigning the drug is time-consuming, expensive and inefficient, and potential new drugs are more prone to failure than those that are already known.

A 2007 paper in Nature by David Newman et al. suggested that despite two decades of combinatorial chemistry, there has been no increase in the number of lead or drug candidates from synthetic sources. Big pharma is under pressure to find new therapeutic products: they have a shrinking product pipeline, patents are expiring on their blockbuster drugs and drug discovery timelines are getting shorter. The increasing costs associated with combinatorial chemistry, combined with its failures have led to pharmaceutical companies to look at other alternatives, namely natural products.

Some natural products display drug-like properties and complement the pool of drugs already discovered with their unique molecular frameworks. Nature offers a greater selection of chemically diverse molecules each with more chiral centres and a greater structural rigidity than synthetic products can offer. And advances in separation techniques have made it easier to overcome some of the practical difficulties previously associated with their use.

As such, the pharmaceutical and biotech companies are turning to natural products as a starting point for new biological tools and drugs. A new approach to drug discovery and a fresh appreciation for natural products have inevitably led to new commercial opportunities – and a new breed of laboratory: the venom lab.

Venomtech are the only commercial venom lab in the UK. It was started in 2010 by Director, Steve Trim, who had previously worked in a UK pharmaceutical company, where he had found it difficult to source tarantula venoms – a problem which he has solved.

“The market is growing, and there’s a huge push in the pharmaceuticals arena to look for new biological tools and new biological drugs.

“There’s a real difficulty getting small molecules to hit ion channels selectively and potently, millions of years of evolution have provided tarantulas with useful venoms which contain great tools that happen to work well on human ion channels. There are tarantula venoms that activate the Trp channels – the capsaicin receptors – ones that block acid sensing ion channels that might be useful in inflammation and others that block sodium and potassium channels which are key modulators in neuronal firing. So tarantulas have the chemical matter, it’s more selective, it’s more potent than many small molecules at ion channels – and that’s our principal product.”

Venomtech – based at the Kent Enterprise Hub at the University of Kent – currently houses over 380 animals, with a further 100 at another facility. In the main lab, there are 80 species of tarantula, 30 scorpion species, seven rear fanged snakes and a few of the true spiders. The other facility houses 47 venomous snake speciess such as black mambas, cobras, rattlesnakes – plus black widows, Brazilian wandering spiders and death stalker scorpions. Key to the business is that the venom is obtained safely, recoverably from the live animals.

“What makes Venomtech different to other labs is that rather than having the venom as a reagent in the freezer we actually have it in the live animals, so we can produce it to order,” said Steve. “If people want microgram scale – or some people even ask for gram scale – we can provide that as we have all the animals in stock.”

“Our key products are going to Europe by bulk, but by number of customers its UK universities principally. Because we’re a new company – we started in March 2010 – we’re still trying to build up our customer base with the pharmaceutical and biotech market,” said Steve. “That’s where we feel there is a real niche for our products and when we talk to the scientific leaders – especially in the fields of ion channels – when they find out what we can provide, they’re really interested in it.”

Venom can be a useful staring point in drug discovery – much like the traditional remedies of old from which scientists discovered the active ingredient and designed new medicines. Venomtech’s key products are 96 and 384 well screening arrays which the pharmaceutical industry uses to look for new biological tools and drugs.

“We principally provide two phylogenetically and geographically diverse arrays – one with 46 snake species, in duplicate and that’s very useful for cancer biology, haematology and looking for new antimicrobials or immunotherapies. Another array – of 46 tarantula species – is a key ion channel targeting tool useful for pain, antimicrobials and insecticides. That’s where our main business started up to provide tarantula venoms for the UK market,” said Steve.

The arrays are used in automated high throughput screens, as well as lower throughput investigational assays The venoms are shipped lyophilised to be re-dissolved and then used to dose the pharmaceutical company’s mammalian (and other) cells under investigation. The venoms supplied by Venomtech are often used in blood coagulation studies, and for investigating how cancer cells behave in the presence of venom. Indeed, research has seen scorpion venom used as a carrier for radioactive iodine and combined with nanoparticles for the treatment of brain tumours.

So for the end user – it couldn’t be simpler: just order your venom and wait.. It is perhaps easy to forget that to harvest the venom means dealing with some of the world’s most deadly animals.

“Collecting venom from the venomous snakes – that is exactly how you see it on the TV. You present the snake to a receptacle that it bites and delivers venom. The key trick of that is holding the snake safely and maintaining a clean product. With the invertebrates we use a similar but modified procedure,” said Steve.

“It’s fairly easy to work with the animals – despite what you think it’s one of the safest environments you could possibly be in around a lot of these animals,” said Chris Loaring, Venomtech’s technician. “I’m surrounded by enormous collection of tarantulas, scorpions, spiders and snakes that could potentially cause harm – but our procedures reduce to the risk to it’s lowest practical level.”

One method to ensure safety when it comes to extracting venom from scorpions, for example, is to anaesthetise them with carbon dioxide. The process – which is a completely recoverable procedure – usually takes 20 minutes, and the scorpion is fully anaesthetised when there is no reaction from its tail. The tail muscle is the last to succumb to anaesthesia, which is logical as this is the scorpion’s primary defence mechanism.

Once anaesthetised, the scorpion is positioned on its back, ready for the extraction procedure. The animal is out for about 15 minutes, providing plenty of time for venom collection. After this, the protein content is analysed and standardised prior to freeze-drying, ready for shipping to customers and use in the drug discovery process.

The use of natural products like venom offers a completely different paradigm that could replace the current R&D model for Big Pharma. Even if it is as a supplementary, labs like Venomtech are well-placed to serve with the changing needs of the pharmaceutical and biotech industries.

The Author

Kerry Taylor Smith Kerry is web editor of Laboratory News and has a degree in Natural Sciences from the University of Bath