HONG KONG ­– International researchers led by the Shanghai Institute of Materia Medica (SIMM) at the Chinese Academy of Sciences have mapped the detailed structure of a receptor with a key role in platelet activation and blood clotting, which has important implications for development of new treatments for cardiovascular and possibly other diseases.

In two papers published in the May 1, 2014 issue of Nature, researchers led by Zhao Qiang, a professor at SIMM, provide a detailed map of the P2Y12 receptor, a human Gi protein-coupled receptor (GPCR).

One of eight members of the P2Y family of receptors in humans, the P2Y12 receptor is one of the most important clinical drug targets for the inhibition of platelet aggregation, although the agonist/antagonist recognition and function of this key receptor have so far remained poorly understood at the molecular level.

"This new work will not only deepen [our] understanding of activation of this receptor super-family, but will also provide invaluable insight into the improvement and development of novel P2Y12 [receptor antagonists] targeting cardiovascular and other diseases," said Zhao.

The receptor structures were mapped by SIMM researchers using advanced X-ray crystallographic and computational techniques.

Inappropriate activation of blood platelets can result in life-threatening conditions such as unstable angina, myocardial infarction (MI) and stroke, which together are responsible for a considerable global health and economic burden.

Several anti-thrombotic drugs that target the P2Y12 receptor have now received approved from the FDA for the prevention of stroke and MI.

Such treatments are critical in the prevention of the thrombotic complications of acute coronary syndromes such as MI and percutaneous coronary interventions, notably balloon angioplasty to clear stenotic or narrowed coronary arteries.

These agents include the prodrugs Plavix (clopidogrel, Bristol-Myers Squibb Co and Sanofi SA) and Effient (prasugrel, Eli Lilly and Co) and the nucleoside analogue Brilinta (ticagrelor, Astrazeneca plc), which acts directly on the P2Y12 receptor.

However, certain limitations associated with these antiplatelet drugs, in particular the long half-life of Plavix and the side-effects of Brilinta, which can cause dyspnea in some patients, indicate an unfulfilled medical need for the development of a new generation of P2Y12 receptor inhibitors.

Plavix and Effient "are both prodrugs that need to be metabolized before they can irreversibly bind to the P2Y12 receptor," Zhao told BioWorld Today, noting that certain individuals, including up to approximately one-third of those taking Plavix, lack the corresponding metabolic pathways. "These patients respond very weakly to these drugs," he noted.

Another major drawback of the currently available oral antiplatelet agents concerns their long half-lives, particularly that of Plavix, which makes these agents difficult to use in clinical practice.

"Because they bind irreversibly to the [P2Y12] receptor, these drugs have a half-life of as long as around 7 days," said Zhao. "This means that a patient would need to wait for over a week [in order] to avoid major bleeding problems before any procedure could be undertaken, no matter how urgent their cases were," he told BioWorld Today.

Given these limitations, there remains plenty of development activity in the area of more effective antiplatelet drugs, said Zhao, citing as examples the potent new reversible P2Y12 receptor antagonists cangrelor (The Medicines Co) and elinogrel (Portola Pharmaceuticals Inc. and Novartis AG), both of which have fast onset and offset of action and are therefore promising candidates for cardiovascular protection.

"Even though the clinical trials on cangrelor were stopped at phase III last year, these developments still reflect an unfulfilled market and the requirement for better drugs," Zhao told BioWorld Today.

However, efforts to develop better antiplatelet drugs have so far tended to have been impeded by a poor understanding of the interaction between the receptor and the drug ligand molecule binding with it.

The two Nature studies describe for the first time the structure of the P2Y12 receptor, both in complex with a full agonist and with a novel reversible non-nucleotide P2Y12 receptor antagonist known as AZD1283, which was discovered and developed by Astrazeneca plc.

Combining the comprehensive knowledge gained from the three structures, the researchers have achieved a detailed understanding of the mechanism of recognition of different types of drug ligands by the receptor.

In addition, the structural and docking mechanism studies should provide valuable insight into the pharmacology and mechanisms of action of agonists and the different classes of antagonists, not only for the P2Y12 receptor, but also potentially for other closely related P2Y receptors.

"What we've learned from this research could pave the way for the creation of drugs with fewer limitations and health risks," said Kenneth A Jacobson, a senior investigator in the Laboratory of Bioorganic Chemistry of the NIH Intramural Research Program in Bethesda, Maryland.

While Zhao concedes that this research is presently of limited clinical significance, he point out that the findings hold promise for future developments. "Right now, this research could not be used directly in clinical [practice], but will greatly accelerate the process of improving current drugs or developing new drugs targeting [the P2Y12] receptor."

In future, "we will keep working on [elucidating] more structures of this receptor. We have observed the exciting open and closed state of the receptor, and this has really expended our knowledge of this receptor super-family.

"However, we feel that there are some intermediate states existing and we will try to obtain more structure of the P2Y12 receptor in complex with different ligands to achieve a more comprehensive understanding of this receptor," Zhao told BioWorld Today.

Having achieved that, "we will try to collaborate with computational scientists, chemists and researchers in order to try to [develop] better drugs against thrombotic diseases," he concluded.