Target identification among repurposed drugs to address apicomplexan parasite-mediated diseases – ApiNewDrug

The ApiNewDrug project is looking for drug alternatives against zoonoses transmitted by two apicomplexan parasites, Toxoplasma and Cryptosporidium, responsible for toxoplasmosis and cryptosporidiosis respectively. These orally transmitted parasites have a significant impact on human and domestic animal health, their control can only be achieved through an integrated "One Health" action. Toxoplasmosis is a usually mild disease in immunocompetent humans that can turn into a major threat to the unborn and to immunocompromised people e.g. with acquired immunodeficiency syndrome (e.g. AIDS) or under chemo- and graft rejection therapies. In livestock, it can be the source of abortions leading to economic losses. Contamination occurs via ingestion of cysts (present in raw/undercooked meat) or oocysts contaminating plants or water. Cryptosporidiosis consists of acute gastrointestinal infections in immunocompromised people and young children, aggravated by malnutrition and leads to high morbidity in developing countries. Cryptosporidium also causes epidemics in industrialized countries due to high resistance to disinfectants other than ozone. Widespread in farms, C. parvum is also one of the two main causes of diarrhea in calves, inducing substantial economic losses to farmers and a source of contamination for humans.
Despite the severity of the symptoms associated with these zoonoses, few treatments are available and their efficacy needs to be improved, especially in people with compromised immune systems. To enrich the therapeutic antiparasitic arsenal, an effort in the search for new compounds / target pairs is imperative. This knowledge will also provide a better understanding of the resistance mechanisms that might arise from the widespread use of drugs to treat human and veterinary clinical cases.
Drug repositioning is the process of finding a new therapeutic indication for drugs approved by the health authorities (e.g. the Food and Drug Administration (FDA)) outside their original indication. It thus saves significant investments of time and money in the development of new drug candidates. This project capitalizes on solid preliminary results provided by the partners. We have screened a library of FDA-approved drug candidates and identified novel compounds that inhibit the growth of Toxoplasma and Cryptosporidium in the nanomolar range with excellent selectivity indexes.
One molecule has already been identified as active against emblematic parasites of human (Plasmodium) and animal (Eimeria) infection, opening the way to the development of pan-apicomplexan treatments. In ApiNewDrug, we will explore the molecular targets of the best candidate molecules by chemogenomics and validate them by CRISPR/cas9-based editing of the parasite’s genome using the trackability of Toxoplasma and the recent advances in genetic manipulation for Cryptosporidium. We will then solve the crystallographic structure of molecules in complex with their target protein to investigate at an atomic-scale the modus operandi of the most promising compounds. The validation of the lead compounds will finally be carried out in vivo with animal models and targets of Toxoplasmosis and Cryptosporidiosis in order to produce a proof of concept for their future use in clinic.