Ubiquitin conjugating enzymes as novel drug targets in Leishmania

Leishmania parasites cause the neglected tropical disease, leishmaniasis, and are responsible for extensive morbidity, mortality, and economic hardship. Every year 1.3 million people are affected by leishmaniasis, of which 20,000 patients die. Treatment is difficult as parasites evade the immune system by hiding in host blood cells. With a meager outlook on efficacious vaccines, treatment relies on chemotherapy. Current chemotherapy is limited, toxic and increasingly ineffective due to drug resistance. Novel targets and new safe, efficacious drugs are urgently needed. This project addresses this unmet medical need. The company UbiQ has developed reagents that for the first time allow the visualisation of the activity of ubiquitin conjugating enzymes, which play a critical role in maintaining a healthy condition of a cell. This allows researchers to now identify and explore these enzymes as potential drug targets. This project aims to identify and validate variants of these enzymes, which are present in Leishmania parasites, as drug targets for treating leishmaniasis. The function of leishmanial ubiquitin conjugating enzymes will be explored and the efficacy of potential inhibitors of these enzymes, developed by UbiQ, will be investigated. This project further aims to investigate whether inhibitors can be developed, which are specific for leishmanial variants of ubiquitin conjugating enzymes over those present in the mammalian host cell. Understanding parasite versus host selectivity will also be helpful for the development of anticancer drugs selectively inhibiting tumour related mammalian ubiquitin conjugating enzymes over ‘normal’ variants present in healthy cells.