The renin-angiotensin system
Cardiovascular functions are finely tuned in mammals, notably by a hormonal and enzymatic regulatory system known as the renin-angiotensin system. In this system, several reactions take place in cascade, leading to changes in blood pressure:
- conversion of angiotensinogen to angiotensin I by renin ;
- the conversion of angiotensin I to angiotensin II by angiotensin converting enzyme (ACE);
- the action of angiotensin II on two G protein-coupled receptors: AT1 and AT2.
A NEED for NEW BLOOD PRESSURE MEDICATION?
In 30% of cases, the treatments prescribed for hypertension do not work or are very poorly tolerated and are discontinued. Two of the five classes of hypertensive drugs target ACE (ACE inhibitors) or AT1 (competitive AT1 receptor inhibitors). They can cause serious adverse effects. New treatments that are more effective and have fewer side effects need to be devised, provided we have a good understanding of the mechanisms involved in the renin-angiotensin system. However, the signalling pathways involving AT1 and AT2 are still relatively poorly understood, due to a lack of suitable tools for studying these receptors.
A team from the Laboratoire de Pharmacologie Expérimentale et Moléculaire (SIMoS/DMTS) has been working for several years to identify animal toxins with pharmacological properties. It has helped to build a synthetic toxin library (Venomics, which contains more than 20,000 toxin sequences) and is able to screen it against a target of interest. It was therefore natural for them to search this library for an AT1 and AT2 ligand (screening around 900 animal toxins). They identified A-CTX-cMila, a 7-residue cyclic peptide from Conus miliaris, active on both AT1 and AT2 receptors, but with 100 greater affinity for AT1. Its characterisation shows that it acts as an AT1 antagonist and has no agonist or antagonist effect on other G protein-coupled receptors tested.
A-CTX-Mila is the first animal toxin known to be active on angiotensin II receptors. Relatively easy to produce, A-CTX-cMila is a very interesting tool for pharmacological studies. It could be the spearhead of a new class of cyclic toxins with high pharmacological potential.
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