Development of new, efficient and ecofriendly rodenticides to control rodent outbreaks – ROC

Rodent management is essential for health and economic issues. This management is very often based on the use of rodenticide anticoagulants (AR) facing 2 major problems, i / the resistance phenomena due to mutations of the target enzyme of the ARs, VKORC1, and ii / their ecotoxicity due to their long persistence and their non-specificity of action. Because of these 2 problems, authorities are sometimes without solution against rodent outbreaks. The development of new rodenticides is therefore essential. The specifications of such molecules are complex: the molecules must have a delayed effect to prevent food aversion, an antidote must be available in case of accidental ingestion, they must be specific to species in order to avoid ecotoxicity problems. Targeting the enzyme VKORC1 is a good way to meet these specifications. Its inhibition allows a delayed effect and this inhibition can be quickly countered by the use of vitamin K.
Recent advances in the structural and functional understanding of VKORC1 now allow the development of effective, species-specific VKORC1 inhibitors that can overcome resistance problems. These new molecules could target the catalytic site of VKORC1 or prevent the activation of VKORC1.

The ROC project is a multi-disciplinary drug-design study aiming at:
-identifying the redox partner of VKORC1 to propose new toxicological targets based on cellular, molecular and enzymatic studies
-characterizing the 2 interaction sites of VKORC1 that may be targeted by inhibitors and determining the differences between VKORC1 sites of the target and non-target species in order to design species-specific inhibitors by molecular modeling, enzymatic and biophysical studies
-determining the structural and functional consequences of VKORC1 mutations on these sites in order to obtain consensus pockets
- designing, on the basis of these consensus pockets, new inhibitors by virtual chemical library screening, de novo synthesis and activity structure study
- testing the efficacy of these new inhibitors by in vitro, ex vivo and in vivo studies.

The project relies on the high complementarity and synergy between four research teams and one industrial partner with optimal complementarity in their respective scientific expertise. V. Lattard (USC1233, coordinator), a biochemist and molecular biologist, has a strong expertise on VKORC1 enzymes and AR resistance. L. Tchertanov (CMLA-ENS) is a physicist specialized in molecular modelling and numerical simulation of membrane enzymes. Sophie Rahuel-Clermont (IMOPA-CNRS) is an enzymologist and biophysicist with strong expertise in Cys-dependent redox enzymes, Florence Popowycz (ICBMS-INSA) is an organic chemist, and Hervé Caruel (Liphatech) has a unique expertise in production rodent bait.

Scientifically, this project will allow i / a better structural and functional understanding of the enzyme VKORC1, ii / an understanding of the structural consequences of mutations and iii / an exploration of a new VKORC1 inhibition strategy. This project will provide the society with new environmentally friendly solutions for the rodent management. Liphatech, partner of this project will produce and distribute via its global distribution network the new molecules-based products developed in this project, after evaluation of the technical- and economic-feasibility, international patents filings and registration.