Novel Therapeutics for Toxoplasmosis and Malaria Directed to New Parasite Targets – NovoTargetParasite

Current anti-toxoplasmosis drugs have serious limitations: side-effects, low-to-moderate efficacy and poor administration routes. The spread of Plasmodium resistance to artemisinin is now a global health problem. This highlights the desperate need of new classes of drugs, ideally directed to novel targets, that will allow to develop the next generation of antiparasitic agents. Benzoxaboroles are novel boron-based compounds that have gained a big therapeutic interest, notably with the discovery of Kerydin, a FDA-approved antifungal that inhibits leucyl-tRNA synthetase (LeuRS). Here I will investigate the potential of these novel boron compounds to treat infections caused by apicomplexan parasites. We have very recently identified two novel Benzoxaboroles with good activity against the parasites causing toxoplasmosis and malaria. The first one, AN6426, is likely an inhibitor of LeuRS, however its inhibition mechanism remains unknown. The second one, AN3661, has not only potent in vitro activity but also excellent in vivo efficacy to save mice of toxoplasmosis and malaria, and surprisingly appears to inhibit an unprecedented drug target, Cleavage and Polyadenylation Specific Factor 3 (CPSF3). Here, I will use a multidisciplinary approach to validate the molecular targets and to investigate the mechanism of action of these promising compounds. Importantly, we will also screen a novel series of benzoxaboroles against apicomplexan parasites that could lead to the discovery of new drug targets and the structural characterization of new inhibition mechanisms.