They all have an invertebrate and vertebrate host, but there are differences in their distribution, transmission and life cycle. and proteasomal degradation are essential for the viability of eukaryotes and the proteins that mediate these processes are therefore attractive drug targets in trypanosomatids. Here, the current understanding of these processes in trypanosomatids is reviewed. Furthermore, significant recent progress in the development of trypanosomatid-selective proteasome inhibitors that cure mouse models of trypanosomatid infections is presented. In addition, the targeting of the key enzyme in ubiquitination, the ubiquitin E1 UBA1, is discussed as an alternative strategy. Important differences between human and trypanosomatid UBA1s in susceptibility to inhibitors predicts that the selective targeting of these enzymes in trypanosomatids may also be feasible. Finally, it is proposed that activating enzymes of the ubiquitin-like proteins SUMO and NEDD8 may represent drug targets in these trypanosomatids as well. and are the major disease-causing trypanosomatids in humans that continue to pose a major risk to the health of millions of people worldwide, especially among the poorest in rural regions of tropical countries. These eukaryotic parasites are characterized by a single flagellum and a kinetoplast, a DNA containing region that Narciclasine is part of a single mitochondrion (Stuart et al., 2008). They all have an invertebrate and vertebrate host, but there are differences in their distribution, transmission and life cycle. and parasites live exclusively extracellularly in the host, during the early mild stage of the disease in the blood, lymph and interstitial spaces, and during the second stage in the central nervous system leading to severe neurological symptoms. is definitely transmitted by blood feeding triatominae and endemic in Narciclasine Latin America. This trypanosomatid alternates between non-replicating trypomastigotes that circulate in the blood and dividing amastigotes, a form with only a very short flagellum, in the cytoplasm of mammalian cells after escape from a lysosomal compartment. Whereas the initial symptoms of a illness are often slight and undetected, a lifelong illness is made that in 30% of instances prospects to a chronic phase of disease with severe damage to the heart and digestive system. Leishmaniasis is caused by more than twenty varieties of that are found common throughout the world with the majority of disease cases happening in Asia, Africa, and Latin America. Leishmania parasites are transmitted from the bite of a sandfly that injects the promastigote metacyclic form, which after becoming taken up by phagocytic cells, transforms into amastigotes that replicate inside the phagolysosome. Leishmaniasis consists of a spectrum of human being diseases with symptoms varying from self-limiting ulcers to the damage of mucocutaneous surfaces, to the fatal visceral leishmaniasis. With the Narciclasine exception of that Capn1 primarily infects humans, these pathogenic trypanosomatids have animal reservoirs that include small and home animals, which makes the control of their transmission very difficult. Early analysis and effective medication are consequently of the Narciclasine utmost importance, but only a handful of medicines is available, most of which have been in use for many decades and have severe shortcomings in delivery, toxicity and effectiveness (Bilbe, 2015; Rao et al., 2018). However, the past 15 years have seen various important initiatives that have improved the visibility of these neglected tropical diseases, enabled collaborations between market, academia and the public sector for drug development on a not-for-profit basis, and improved the availability of study funding. This has resulted in significant successes particularly in the treatment of HAT for which a safe oral treatment has now become available (Dickie et al., 2020; Neau et al., 2020). More clinical tests are ongoing, also for Chagas disease and Leishmaniasis treatments, but failures of medical tests have also been reported. Given the general low success rate of drug development, its low predictability and very long duration plus the added anticipation of future drug resistance, multiple parallel attempts in study, drug finding and development are required to generate a considerable pipeline of anti-trypanosomiasis drug candidates. New mixtures of existing medication as well as the optimization of dosing regimes have already resulted in quick improvements in treatments. Furthermore,.