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).
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 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."
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.
Edwin Chen, Wellcome Trust (Jul 2016), £98,341
Stefan Kepinski, Michelle Peckham, BBSRC (Apr 2016), £461,760
David Brockwell, Sheena Radford, BBSRC (Apr 2016), £358,570
Ryan Seipke, BBSRC (Apr 2016), £340,536
Neil Ranson, Mark Harris, Ade Whitehouse, Peter Stockley, Sheena Radford, Alan Berry, Wellcome Trust (Mar 2016), £1,000,000
James Duce, Alzheimer's Society (Mar 2016), £84,834
Thomas Edwards and colleagues in the School of Chemistry, EPSRC (Feb 2016), £2,228,732
Patricija Van Oosten-Hawle, Wellcome Trust (Feb 2016), £89,900
William Hoppitt, EU (Feb 2016), £34,345
Mark Harris, Thomas Edwards, John Barr and colleagues from the School of Chemistry, Wellcome Trust (Jan 2016), £204,959
Katie Field, BBSRC (Jan 2016), £830,381
Alan Berry, Alex Breeze, Adam Nelson, BBSRC (Jan 2016), £479,490
Sarah Calaghan, Isuru Jayasinghe, BHF (Jan 2016), £52,050
Paul Knox, BBSRC (Jan 2016), £40,000
Andrew Smith, Rosetrees Trust (Jan 2016), £20,000
Richard Bayliss, Cancer Research UK (Jan 2016), £10,000
Richard Bayliss, MRC (Jan 2016), £8,000
Richard Bayliss, BBSRC (Jan 2016), £8,000
Joe Cockburn, Royal Society (Dec 2015), £14,960
Katie Field, Royal Society (Dec 2015), £14,700
Stephanie Wright, Kay Kendall Leukaemia Fund (Dec 2015), £207,286
Zahra Timsah, Royal Society (Nov 2015), £15,000
Jessica Kwok, Wings For Life Spinal Cord Research (Nov 2015), £134,981
Alan Berry, Wellcome Trust (Oct 2015), £752,365
Julie Aspden, MRC (Oct 2015), £633,020
Steve Sait, NERC (Oct 2015), £386,061
Urwin, Howard Atkinson, BBSRC (Oct 2015), £200,293
Helen Miller, ABNA Ltd (Oct 2015), £115,000
Mark Harris, Royal Society (Oct 2015), £74,000
Eric Hewitt, Andrew Macdonald, Yorkshire Kidney Research Fund (Oct 2015), £46,621
Christine Foyer, Royal Society (Oct 2015), £12,000
Dave Westhead, Bloodwise (Sep 2015), £664,109
Ade Whitehouse, Alison Ashcroft, Ian Carr, BBSRC (Sep 2015), £438,975
Shaunna Burke, Andrea Utley, Sarah Astill, Arts Council of England (Sep 2015), £80,594
Samit Chakrabarty, Ronaldo Ichiyama, Intl Foundn for Research in Paraplegia (Aug 2015), £93,000
Helen Miller, Agriculture & Horticulture Develpmnt Brd (Aug 2015), £63,560
Tim Benton, M & W MACK LTD (Aug 2015), £48,711
Eileen Ingham, John Fisher, EPSRC (Jul 2015), £1,458,439
Anastasia Zhuravleva, BBSRC (Jul 2015), £483,019
Alex O'Neill, MRC (Jul 2015), £249,822
Ade Whitehouse, Richard Foster, Cancer Research UK (Jul 2015), £201,034
Ronaldo Ichiyama, Jim Deuchars, Sue Deuchars, Wings For Life Spinal Cord Research (Jul 2015), £123,895
Helen Miller, ABNA Ltd (Jul 2015), £22,968
Martin Stacey and colleagues in FMH, MRC (Jun 2015), £426,475
Adrian Goldman, Sarah Harris, Roman Tuma, BBSRC (Jun 2015), £420,693
Elwyn Isaac, EU (Jun 2015), £238,915
Christine Foyer, BBSRC (Jun 2015), £160,401
Adrian Goldman, EU (Jun 2015), £116,331
David Brockwell, Sheena Radford, Innovate UK (Jun 2015), £113,378
Yoselin Benitez-Alfonso, EPSRC (Jun 2015), £93,672