Clinical trial of DprE1 inhibitors: from bench to bedside

Abstract The DprE1 enzyme is a viable target for creating new antituberculosis (TB) medications. It is essential for synthesizing the mycobacterial cell wall's important components called arabinans. Inhibition of DprE1 can lead to the cell lysis of Mycobacterium tuberculosis (Mtb). Several DprE1 inhibitors have been developed and tested in preclinical studies. BTZ043, PBTZ169, TBA-7371, and OPC-167832 are some of the inhibitors that have exhibited excellent activity against TB both in vitro and in animal models. The mode of action is unique and different from the first-line drug ethambutol (EMB) (inhibits the arabinosyltransferases). TBA-7371 completed phase 2 trials, and the phase 2a clinical trials for PBTZ169 were terminated due to low enrolment. Meanwhile, BTZ043 and OPC-167832 are currently in phase 2 trials. This review provides an overview of the discovery, synthesis, preclinical, and clinical studies of DprE1 inhibitors, which have entered clinical trials. Article Highlights DprE1 inhibitors are a new class of anti-TB drugs that target the DprE1 enzyme. DprE1 enzyme is essential for the synthesis of the Mtb cell wall. Four DprE1 inhibitors are in clinical trials.