Cloning of the P2Y receptor class leads to the development of important new therapies

Cloned receptors within the P2Y class, the molecular structure of which was established at UCL, are used increasingly as therapeutic targets for a variety of disorders. These include new drugs to reduce the risk of thrombotic events and to relieve the symptoms of dry eye disorder.

Adenosine 5'-triphosphate (ATP) was originally considered an exclusively intracellular energy source. Against consensus opinion, Professor Geoffrey Burnstock (UCL Cell & Developmental Biology) pioneered the notion that ATP and its derivatives can also act as extracellular messengers. Several decades of research have proven his groundbreaking theory correct and today the research he founded on purinergic signalling is a vast and expanding field of biomedical study. We now know that such signalling occurs in many cell types throughout the body, including neurons, smooth muscle cells, epithelial cells, erythrocytes, immune cells and sperm.

Professor Burnstock was the first to define three distinct classes of purinergic receptor: P1, P2Y and P2X receptors. Important roles for these receptor types have been identified in development (from cell cycling to migration), normal physiology (from pain sensation to bladder contraction) and pathology (from arthritis to cancer).

In 1993, Professor Burnstock worked with Eric Barnard at the Royal Free Hospital and Professor Trevor Smart at the School of Pharmacy (both now part of UCL) to clone the first P2Y G protein-coupled nucleotide receptor. The work established for the first time the molecular structure of this class of receptor and has led to the cloning of seven other P2Y receptors.

Further work in the Burnstock Lab identified roles for P2Y receptors in, among other things, human platelet shape change and mucus secretion. These discoveries have since been influential in the successful development of new drugs to reduce the risk of thrombotic events in people suffering from myocardial infarction or ischaemia and to relieve the symptoms of dry eye disorder.

Every year arterial blood clots lead to approximately 90,000 heart attacks and 150,000 strokes in the UK. The historical use of anticoagulants such as aspirin and warfarin to reduce the likelihood of blood clotting in high risk cases has been subject, in recent years, to increasingly critical scrutiny of the widespread and sometimes severe unwanted side effects of these drugs. Professor Burnstock's research has supported the development of new drugs to prevent platelet aggregation, notably clopidogrel and its derivative ticagrelor, which are now used widely and successfully to treat and prevent thrombosis and stroke.

Clopidogrel (trade name Plavix, marketed by Bristol-Myers Squibb and Sanofi) is indicated for the prevention of thrombotic events in patients suffering from symptomatic atherosclerosis, acute coronary syndromes and ischaemic stroke, or after placement of intracoronary stent. It may also be used as an alternative antiplatelet drug for patients who are intolerant to aspirin. Plavix is marketed worldwide to nearly 110 countries, with global sales of $7.09 billion in 2011.

Ticagrelor (trade names Brilique, Possia and Brilinta, produced by AstraZeneca), which acts faster than clopidogrel, is indicated for the prevention of thrombotic events such as stroke or heart attack in patients with acute coronary syndrome, or who have recently had an ischaemic stroke. Treatment of acute coronary syndrome with ticagrelor significantly reduces the rate of death from vascular causes, myocardial infarction or stroke. Brilinta is now included in seven sets of cardiovascular treatment guidelines produced by leading medical organisations across the world: two in Europe, four in the USA and one in Canada. It has been approved in 65 countries and its use is currently being reimbursed in 21 of them. It is now on formulary at more than 80% of the top 400 hospitals in the USA and its 2012 sales were $89 million.

Although its effects are less serious than those of arterial blood clots, the eye disease keratoconjunctivitis sicca - or dry eye syndrome - can also have significant impacts on quality of life. This relatively common disorder, which is caused by either decreased tear production or increased tear film evaporation, can be so painful that patients resort to surgery.

Professor Burnstock's characterisation of the P2Y receptor class made it possible to identify specific agonists of the P2Y2 receptor which evokes mucus secretion. In turn, this allowed the development by Inspire Pharmaceuticals of diquafasol (Diquas), an ophthalmic solution shown in clinical trials in Japan to improve dry eye symptoms by promoting secretion of mucin and water, thereby bringing the tear film closer to a normal state. The product was launched in Japan in 2010, netting Inspire Pharmaceuticals a milestone payment of $1.25 million in the fourth quarter of the same year.