Spiders, snakes and scorpions, with probably several tens of thousands of species, or even more, have the ability to synthesize venom abounding with several hundreds of peptides, which is their weapon for predatory and protective purposes. Animal toxins amount to an estimated 40 million. However, to date only 3,000 have been identified, of which maybe 1,000 have been characterized pharmacologically. At the CEA Center in Saclay, Denis Servent's team at the Saclay Institute for Biology and Technologies (iBiTec-S) is one of world's few in this field that does not consider venom as a source of toxic toxins but as a peptide bank, which can be used to find very interesting - specifically therapeutic - activities for humans. Nicolas Gilles, a pharmacologist on the team, has been working on this subject for a dozen years or so.
A Green Mamba, Dendroapsis angusticeps Crédits : CEA
In the early 90's, Nicolas Gilles joined the CEA as a technician at a protein marking laboratory. He gradually climbed the professional ladder, first by passing his engineering degree at the Conservatoire National des Arts et Métiers (CNAM) and then by writing his Ph.D. under the supervision of a specialist in scorpion toxins. "I went from protein biochemistry to ion channel pharmacology," recapped the biochemist who is now working on molecular pharmacology. When he discovered the world of animal toxins during his thesis, a dozen people were already working on the subject. "It's an easy-to-handle mini-protein, which can be used as a base for the study of protein-protein interaction," he recalled. This is how they are now presented while also using them as a marking or contrast tools for the study of their target receptors.
The different types of venom have been studied for a long time, with a focus on understanding why they are toxic. That is why most of the currently known toxins are active on the ion channels controlling nervous transmission or muscle contraction. In 2003-2004, Denis Servent and Nicolas Gilles decided to share the work. The former focused on the study of active toxins on G Protein-Coupled Receptors (the renowned GPCRs that earned Americans Robert Lefkowitz and Brian Kobilka the 2012 Nobel Prize for Chemistry) with a focus on a handful of active toxins on muscarinic receptors. "What I did was to take a fresh look at the basis of the study of venom, focusing my research on therapeutic development," Nicolas Gilles explained. He observed the following, at best, only about 10% of what is in the most studied venom is known. This means that we know nothing about the potential pharmacological activities of 90% of the toxins in the different types of venom.
Starting from this observation, the CEA researcher developed a venom screening technique on GPCRs. Why did he focus on these receptors? "It is now the prime therapeutic target that large pharmaceutical firms are tackling. Actually, there is huge need for selective ligands to develop improved quality drugs," he explained. His research on the four types of venom of the four species of African mambas led him to discover several toxins, including one from green mamba (Dendroapsis angusticeps) venom that has an "extremely original activity and very promising therapeutic potential," the researcher exclaimed. Now the toxin has to be transferred to the pharmaceutical industry, the hardest step, given that only one molecule out of the 1,000 molecules with a therapeutic activity will be marketed. Another option is to use the toxin as a scientific tool to gain a firmer grasp on how a receptor works and develop marking or contrast agents for diagnostic purposes. For the time being, Nicolas Gilles is working on other toxins that act on kidneys. "We are hopeful that we will reach developments and perhaps file a patent," he said, without giving any further details... for now.