By Nuala Moran
BioWorld International Correspondent
LONDON Astex Technology Ltd. said it solved the first 3-dimensional crystal structure of a human cytochrome P450 enzyme involved in drug metabolism, a discovery that will make it easier to rationally design drugs that reduce metabolic and toxicity problems.
At the same time the company announced that it raised a further 5.7 million from existing investors, taking its total funds raised in 2001 to 28.4 million (US$41.3 million).
Cytochrome P450s, the most significant group of drug-metabolizing enzymes in humans, are the cause of adverse reactions to many marketed drugs, while many compounds fail in development because of the way they interact with P450s. Certain drugs also may be ineffective or even harmful as a result of patient-specific variations in cytochrome P450s.
Harren Jhoti, co-founder and chief scientific officer of Astex, based in Cambridge, UK, said P450 proteins are among the most difficult types of structures to solve as they are large and complex, and partly embedded within lipid membranes. Once released from the membrane they are unstable.
By understanding how these proteins recognize drug molecules at the atomic level, we will rationally design drugs with better metabolic and toxicity profiles and thus an improved chance of making it to the market, he said.
Solving the structure is a validation of Astex s high-throughput X-ray crystallography platform. The company said it has industrialized X-ray crystallography, developing techniques for producing proteins and crystallizing them, then going from crystals to structure automatically, cutting the data analysis and interpretation time from weeks to minutes.
This breakthrough further demonstrates the effectiveness of our proprietary technology, Jhoti said. We will build on this success and continue our progress with the other key members of this protein family.
In May, Astex announced a P450 research collaboration with AstraZeneca plc. Now that Astex has solved this first structure, AstraZeneca will be able to check how its compounds interact with this enzyme and tweak them accordingly. Astex expects to find other pharmaceutical partners for its P450 program and will use the data internally to enhance the properties of its own compounds. Astex also has a deal with the Janssen Research Foundation, of Beerse, Belgium, a subsidiary of Johnson and Johnson, to solve an unnamed crystal structure.
Astex was established in 1999 with 800,000 seed funding and subsequently raised 3.3 million in the form of a loan. The 22.7 million it raised in May was one of the largest first-round fundings by a UK biotechnology company. The money came from Advent International, of Boston; Alta Partners, of San Francisco; and GIMV, of Antwerp, Belgium. The 5.7 million top-up financing announced in December came from the same investors and was larger than planned.
CEO Tim Haines said the additional funding was a further endorsement of the company s potential. These funds put us in a strong position to rapidly progress the novel drug discovery approaches being developed at Astex.