It is widely appreciated that GPCRs have been the most successfully exploited class of targets for the development of drugs. Despite, only 15% of the non-olfactory GPCRs are the targets of a clinically used medicine. In many cases, this reflect a lack of understanding of the basic underpinning biology of many GPCRs, as well as a paucity of pharmacological tool compounds.
It is also widely appreciated that animal venoms represent a huge and promising source of bioactive peptides. Despite, only a tiny fraction of this natural resource has been characterized. Given the wide diversity in structures and sequences, it is more than likely that animal toxins may be actives on many families of targets.
We made our specialty the systematic exploration of venoms to identify toxins active on GPCRs in relation to unmet medical needs.
The type 2 vasopressin receptor is a validated therapeutic target for some renal diseases. Nine Kunitz peptides, named the mambaquaretins, were discovered in the four mamba venoms. These peptides form a distinct phylogenic group in the Kunitz family with a new function and mode of interaction with the V2R. MQ-1, the most affine toxin, was validated as a drug candidate. After optimization, its therapeutic development process is underway.
All the GPCR toxins that we identified are very much in the minority in their venoms. We succeeded to fish them thanks’ to a use of large amount of material. This strategy is not compatible with the majority of the venomous animals, due to their small sizes. The VENOMICS project proposes a new paradigm compatible with the exploration of 100% of the biodiversity. The resulting synthetic bank of 3600 natural toxins was successfully screened on GPCRs. The future of GPCRs toxins is very promising for science and medicine and still represents a new ground of venom research.