Résumé
Malaria is the most important human parasitic disease, with more than 200 million cases every year and 450 thousands deaths, 90% of them in Africa (WHO, 2018). Plasmodium multi-resistance, including against artemisinin, seriously threaten malaria treatment and control. There is an urgent need to find new drugs targeting essential steps of the parasite life cycle. The egress of merozoites from their host cells (hepatocytes, erythrocytes) is such an essential step and is governed by the SUB1 peptidase, defining SUB1 as a promising drug target.(a,b) Importantly, SUB1 inhibitors would be of high interest in both prevention (action on the infected hepatocytes) and therapeutic (action on the infected erythrocytes).We are developing two series of pseudo-peptidic inhibitors of SUB1 based on its natural substrates (SERA) and its catalytic mechanism. The first series corresponds to monomeric inhibitors, whereas the second includes macrocyclic dimeric analogues of the best monomers, in which the two monomers are separated by variable linkers. This strategy aimed to improve the inhibitory potency, the metabolic stability and cell membranes crossing. Few compounds inhibited PvSUB1 with Ki in the 50-100 nM range and some showed moderate activity in an invasion/egress cell assay. Finally, the crystallographic structure of several complexes was determined at high resolution, facilitating the structure-based design of future compounds. We will present and discuss the solid phase synthesis and biological and structural evaluation of these SUB1 inhibitors.