Snake Venom for the Treatment of Heart Disease?
Snake venom could be a promising starting point for the design of new heart disease drugs. This has been proposed by researchers of the University of Bath who have identified two possible new routes for developing novel drugs for high blood pressure and heart disease.The research, published in the prestigious Nature journal Scientific Reports, was led by Professor K. Ravi Acharya in collaboration with the Universities of Leeds and Cape Town, South Africa.
The scientists created images of the 3D molecular structures of two peptides, including one from snake venom, that inhibit angiotensin-I converting enzyme (ACE), a key protein that regulates blood pressure. ACE inhibitors, such as the drug Captopril, are taken by millions of people in the UK to treat high blood pressure (hypertension) and heart disease. However the drugs cause side effects such as a persistent cough and angioedema (swelling of the face and throat).
How to Block ACE
In this Medical Research Council funded study, the team produced images of a snake venom peptide BPPb binding to ACE. Although this peptide has been identified previously as a possible template for drug design, it is the first time scientists have been able to see at the molecular level how the peptide binds to ACE and blocks its action.
Professor Ravi Acharya, from the Department of Biology & Biochemistry at Bath, said: "We found that the BPPb peptide binds to a major portion of the active site of the ACE molecule pushing out a zinc atom which is essential for its correct functioning. "This is the first time we've observed zinc-independent inhibition of ACE, and so these findings highlight a very exciting opportunity to design new antihypertensive drugs based on this peptide."
Next Generation ACE Inhibitors
In addition, the researchers looked at the structure of angiotensin-II (Ang-II) bound to ACE. Ang-II is a hormone produced by ACE that also inhibits it, creating a feedback loop that stops levels of Ang-II getting too high.
Professor Acharya commented: "We already knew that Ang-II blocks ACE, but not how it does this at the molecular level.
This study has shown for the first time how ACE self-regulates by producing a molecule that obstructs its active site when the concentration reaches a certain level." The next step is to use this structural knowledge as a basis for accelerating the on-going work carried out by Professor Acharya and his collaborators on the development of next generation ACE inhibitors that have improved efficacy and fewer side effects. The scientists will first use computers to predict the action of different drug designs, then take the best drug candidates and test them in vitro, followed by tests in animal models for hypertension.
Masuyer G. et al.: Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides, Scientific Reports 2, (2012) doi:10.1038/srep00717