Toward Chemical Validation of Leishmania infantum Ribose 5-Phosphate Isomerase as a Drug Target

Neglected tropical diseases caused by kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi, and spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely outdated, inadequate, and face mounting drug resistance from the causative parasites. Thus, there is an urgent need for drug discovery and development. Target-led drug discovery approaches have focused on the identification of parasite enzymes catalyzing essential biochemical processes, which significantly differ from equivalent proteins found in humans, thereby providing potentially exploitable therapeutic windows. One such target is ribose 5-phosphate isomerase B (RpiB), an enzyme involved in the nonoxidative branch of the pentose phosphate pathway, which catalyzes the interconversion of d-ribose 5-phosphate and d-ribulose 5-phosphate. Although protozoan RpiB has been the focus of numerous targeted studies, compounds capable of selectively inhibiting this parasite enzyme have not been identified. Here, we present the results of a fragment library screening against Leishmania infantum RpiB ( RpiB), performed using thermal shift analysis. Hit fragments were shown to be effective inhibitors of RpiB in activity assays, and several fragments were capable of selectively inhibiting parasite growth . These results support the identification of RpiB as a validated therapeutic target. The X-ray crystal structure of apo RpiB was also solved, permitting docking studies to assess how hit fragments might interact with RpiB to inhibit its activity. Overall, this work will guide structure-based development of RpiB inhibitors as antileishmanial agents.