Targeting the proteasome in Leishmania donovani: developments from preclinical to Phase I and ii trials

Visceral leishmaniasis (VL), a neglected tropical disease caused by Leishmania donovani and L. infantum, which affects poor areas of South Asia, East Africa, and Brazil, and is fatal if left untreated. Current treatments, including liposomal amphotericin B, miltefosine, paromomycin, and pentavalent antimonials, are limited by emerging resistance, high cost, cold storage, need for parenteral administration. These drawbacks of the currently available therapy entail the development of a safe, short, and oral therapy for VL treatment.

This review summarizes current knowledge of the Leishmania 20S proteasome as a therapeutic target, as it maintains protein homeostasis and exhibits structural variances from the human proteasome that allow selective, parasite-specific inhibition. It covers the preclinical story of GSK3494245 to the story of proteasome inhibitors, especially LXE408, which has progressed from Phase I evaluation to Phase II clinical trials in India and Ethiopia. Collectively, these results place proteasome inhibition as a promising clinical approach that may revolutionize the VL treatment.

Proteasome inhibitors provide strong antiparasitic activity, high selectivity and a potential for oral treatment. If the ongoing clinical trials show safety, efficacy and durable cure rates, proteasome-targeting drugs will revolutionize VL therapy and be a model for drug development against other neglected tropical diseases.