- Toxins from 203 venomous animal species from all over the world have been obtained, sequenced and reproduced. These animals ranged from tiny insects to huge lizards.
- This process involves a new integrated working methodology with high-throughput screening, which exponentially accelerates the discovery of new drugs.
- The objective of VENOMICS was to develop a totally new strategy dedicated to the discovery of animal toxins useful in the development of drugs, primarily for immune system diseases, obesity, diabetes and cardiovascular disease.
Paris, 16 October 2015.- Today in Paris European researchers presented the results of the VENOMICS project, a four-year collaboration involving the identification and sequencing of toxins that had never been studied before, opening the door to the discovery of new drugs based on poisonous substances. In total, the VENOMICS project has analysed samples of venoms from 203 animal species of all different sizes (from tiny insects to huge lizards) from around the world. “To have access to that diversity of species, we have combined scientific expeditions & collaborations, and established particularly efficient commercial relationships (AlphaBiotoxine, Belgium)”, explains Frédéric Ducancel, responsible for the Souring in the VENOMICS project (CEA, French Alternative Energies and Atomic Energy Commission), Paris (France). This allowed the creation of a unique database containing more than 25 000 sequences of toxins, of which 4000 have been produced in vitro. This unique synthetic bank is under screening process and the very first results show 30 validated hits (molecules that give a positive reaction in a trial).
“The other part of the bank will be screened during the next months. In parallel, the identified hits will be characterized in terms of affinity, selectivity, structure and function. Those showing the best properties will be challenged in models of the targeted diseases. In function of the quality of the results, these drug candidates will be patented," explains Nicolas Gilles, project coordinator of the VENOMICS project and researcher at the toxins, channels and receptor team at the CEA (French Alternative Energies and Atomic Energy Commission), in Paris (France).
The European VENOMICS project was partly financed by the Seventh Framework Program (FP7 HEALTH) and its main objective was to investigate, by cutting edge omic technologies, the biggest biodiversity of venoms. In four years, VENOMICS succeed to generate the largest databank rich of 25 000 validated sequences. Until now, there were two large toxin databases: Conoserver, a database of approximately 1500 toxins isolated from poisonous snails, and Aracnoserver, with around 6000 spider toxins. From this database, 4000 sequences have been produced and organized to be compatible with a high-throughput screening (HTS).
The history of pharmacology has already seen examples of venom-based drugs approved and used therapeutically to treat diseases, for example Prialt® (developed from cone snail venom), which is an analgesic, or Byetta® (based on Gila monster lizard salivary), used as an antidiabetic for type 2 diabetes. VENOMICS has laid the groundwork for the continued development of these kinds of therapy.
Accelerating the process of drug investigation
But what is more, the project has demonstrated the "potential of omic technologies" in the search for new drug candidates. The techniques used (de novo proteomics and transcriptomics) have reduced the time required to identify pharmacologically active molecules. Procedures currently used for discovering new drugs require a great deal of money and time, hindering the initial identification of active molecules. VENOMICS has accelerated this process exponentially, paving the way for an unprecedented depth of study that would not have been possible without omic technologies", says Rebeca Miñambres, head of the R&D Projects Department of Sistemas Genómicos, in Valencia (Spain), which was responsible for the development of de novo transcriptomics
When the Venomics project was conceived, one of the keys was to develop a sample analysis process which was much faster than those used in pharmaceutical laboratories to date.
Renaud Vincentelli, Head of Protein Production at AFMB, CNRS–Aix-Marseille Université, Marseille (France), explains: “Animal toxins are peptide up to 120 residues structured by disulphide bridges. Two strategies were chosen for their production. The first one is the chemical synthesis particularly adapted for the production of short peptides, especially with post-translational modifications. We design a specific protocol for HT synthesis and folding of toxins which allowed the production of 1000 toxins, ready to be screened. The second strategy is the recombinant expression. After benchmarking most of the protocols in the literature for the production of toxin in E. coli, and together with the company NZYTech (Lisbon), we developed a new and original protocol that allowed the production, purification and characterization of 4000 recombinant toxins of 35 to 120 residues within six months. Most of the steps involved have been automated on robotics and this explains in part, the hundred fold increases in speed compared to the traditional pipelines of laboratory specialized in the study of recombinant toxins. Furthermore, unlike most protocol published, with this process, the toxins are oxidized and functional already after the purification from the E. coli cultures; this dramatically decreases the time of production. This pipeline is using a unique procedure for all the known families of toxins and represents without any doubt the most efficient production pipeline ever built for toxins production”.
The VENOMICS consortium is composed of a mix of SMEs (NZYTech from Lisbon, Sistemas Genomicos from Valencia and ZealandPharma from Copenhagen) and academic labs (Liege university, Marseille university and the CEA, Paris) and is under the management of Absiskey, Grenoble. This project involved four major steps.
The first step was animal sourcing, to obtain high-quality samples of venom and venom glands from different species. “In the beginning, the animals providing the venom were found through expeditions (French Guiana, Mayotte Island, Polynesia), but in the last year a company specialised in breeding poisonous animals (AlphaBiotoxine, Belgium), including some rare species, was contracted. In addition to “classical” snakes, scorpions, spiders and cone-snails, animals under analysis included scolopender, fishes, a poisonous species of lizard that had never been studied before, an octopus and different insects including bees, wasps, bumble-bees, etc.”, explains Frédéric Ducancel, leader of the sourcing area of the VENOMICS.
The second step was the generation of the sequence database. Subsequently, “the venom was sent to the proteomics team and the venom gland, from which we extracted the RNA, to the team in charge of de novo transcriptomics sequencing. Both teams worked in parallel on the same animal", explains Rebeca Miñambres. Bioinformatic annotation of the resulting transcriptomes was then carried out by the CEA (Marion Verdenaud).
The results obtained by de novo the proteomics and transcriptomics teams were sent to the integration team, which examined the results from both groups to validated the peptides sequences that met the structural criteria defined by the toxicology experts of the consortium.
The third step was the production phase, which involved two techniques: chemical synthesis (amino acid chains) and production in bacteria (introducing the gene of the protein you wish to produce to a bacterium).
Finally, the fourth step was the screening to verify whether they were active against any target related to diseases. According to Frosty Loechel, Director of Molecular Pharmacology, Zealand Pharma, Glostrup (Denmark), who was in charge of the screening phase, "The library of 4000 toxins is currently being screened in a panel of four assays at Zealand Pharma and the CEA. Two of these are phenotypic assays to identify hits that can be developed into drugs for inflammatory diseases, diabetes, or obesity. Two of the assays are target-based assays (5 GPCR and one ion channel), where the screening hits can be developed into drugs for inflammatory, diabetes allergies or autoimmune diseases”. The company plans to continue screening the hits with therapeutic potential after the VENOMICS project has been completed.
Major achievements of the VENOMICS project
- Analysis of 203 different species as diverse as snakes, scorpions, spiders, gasteropods, fiches, insects, scolopendra, cnidarians, octopus and lizard.
- Creation of the largest database reaches of 25 000 sequences.
- Generation of the first bank with 4000 bioactive peptides.
- Already 30 validated hits on target in relation with unmet medical needs.
- These results validate Venomics as an efficient strategy for the identification of rare toxins useful in human health.
Who has taken part in VENOMICS?
CEA Saclay - Coordination, leader in sourcing, bioinformatics annotation & in peptide synthesis
AFMB-CNRS, Université de la Méditerranée - Leader in high-throughput protein production
Absiskey - Project management
Université de Liège - Leader in proteomic analysis
Sistemas Genómicos – Leader in transcriptomic analysis
NZYTech – Leader in molecular biology
Zealand Pharma – Leader in drug development
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