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at the Laboratory of Experimental and Molecular Pharmacology (SIMoS/DMTS) have
identified and characterised an animal toxin as a ligand for angiotensin II
receptors, which are involved in one of the signalling pathways targeted by
antihypertensive drugs. A-CTX-cMila, as it is called, is a tool of choice for
studying the cellular mechanisms controlled by these receptors and could be the
first representative of a new class of toxin with high pharmacological
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:
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.
van Baelen, Xavier Iturrioz, Marion Chaigneau, Pascal Kessler, Catherine
Llorens-Cortes, Denis Servent, Nicolas Gilles and Philippe Robin. Characterization of the First Animal
Toxin Acting as an Antagonist on AT1 Receptor. | International
Journal of Molecular Sciences, 2023, 24, 2330. https://doi.org/10.3390/ijms24032330
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