Researchers have identified two proteins, including one from snake venom that may have applications for developing novel drugs for treating high blood pressure and heart disease. The study was led by University of Bath, in collaboration with the Universities of Leeds and Cape Town.
Published in Nature Scientific Reports, images of 3D molecular structures of two proteins that inhibit Angiotensin-1 converting enzyme (ACE), a key peptide in blood pressure regulation, were created. One of these, the snake venom protein BPPb, (bradikinin-potentiating peptide) had previously been identified as a possible template for drug design, but until now, scientists had not been able to observe at the molecular level how the peptide binds to ACE, blocking its action.
Professor Ravi Acharya, who led the study 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.”
In addition to BPPb, the team also observed 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 prevents ANG-II levels getting too high.
“We already knew that Ang-11 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.”
Millions of people in the UK take ACE inhibitors such as Captopril, to treat high blood pressure (hypertension) and heart disease. Unfortunately, these drugs can cause side effects such as a persistent cough and angioedema (swelling of the face and throat).
Future research will use this structural knowledge to speed up on-going work carried out by the team into developing next generation ACE inhibitors which are more effective and have fewer side effects than current antihypertensive drugs.