Antimalarial drug repositioning in the schistosomiasis treatment based on the selective inhibition of the enzyme dihydroorotate dehydrogenase

Abstract

The repositioning of drugs consists of the evaluation and/or use of existing drugs for treatment of diseases other than those for which they were originally developed. This strategy is of particular interest for the development of new therapeutic strategies, especially for the treatment of neglected diseases, since it allows the evaluation of bioactive potential to molecules which have had their toxicity and bioavailability characteristics previously assessed by clinical trials steps, those representing the highest cost steps in the development of new drugs. In this context, this project aims to explore the potential of molecules with antimalarial action based on the selective inhibition of dihydroorotate dehydrogenase (DHODH), for the treatment of schistosomiasis. DHODH enzyme participates in the biosynthesis of pyrimidine nucleotides de novo pathway, and it is a validated therapeutic target for the treatment of proliferative and parasitic diseases. Previous studies from our laboratory have identified high sequence and structural similarity between the enzymes from Plasmodium falcipurum DHODH (PfDHODH), the causative agent of malaria and Schistosoma mansoni (SmDHODH), the causative agent of schistosomiasis. In addition, cross-inhibition assays using the homologous human enzyme (HsDHODH) demonstrated the ability to identify selective inhibitors for SmDHODH. This project aims at assessing the potential of known PfDHODH enzyme inhibitors, including atovaquone (already on the market) and the DSM265 molecule which is already in clinical trials, as inhibitors of SmDHODH. The best inhibitors will have initially its inhibition mechanism characterized through the use of biochemical techniques, biophysical and X-ray crystallography and will have their potential anti-schistosomiasis evaluated using in vitro and in vivo assays. The results obtained with the development of this would contribute to the validation of DHODH as a target for drug development against schistosomiasis. The possibility of proposing a new strategy to combat schistosomiasis through the antimalarial drug repositioning is also a possibility that should not be ruled out.