Project Portugal 2030

Summary

The dog serves as the natural reservoir for L. infantum, causing Canine Leishmaniasis (CanL). The treatment is long and not effective at clearing infection leading to relapses and consecutive treatment cycles [7]. The treatments are long and often interrupted by toxicity leading to poor treatment compliance. These two phenomena, contribute to the emergence of resistant parasites that have the potential to circulate between humans and animals [8, 9]. Considering that CanL treatment has basically the same active principles as VL, this is a glaring violation of One Health principles potentiating the circulation of drug-resistant parasites. Thus, there is an urgent unmet need to develop new dedicated drugs for CanL [10]. To do so, it is essential to discover new treatment options for CanL. The only orally available option to treat the animals is the same as humans, MLT. The development of orally available drugs is a priority. MLT at its core is a non-optimized lead molecule. PreClinLeish collaborates with Theodora Calegeropoulou, a leader in ether phospholipid research [11-13]. Our combined research efforts have been associated with the development of constrained derivatives that were more active and less toxic than MLT. Further work related to an FCT project PTDC/SAU-PAR/31013/2017 led to the discovery of thiazolidinone as a possible replacement for the phosphate core of MLT. Thiazolidinone is a phosphate mimetic and demonstrated remarkable effects providing molecules that retain superior anti-leishmanial activity against different species and more importantly are active in MLT-resistant strains (Table 1-3) (patent request 01_118291). Moreover, these molecules retain significant oral availability (Table 4). This is a significant breakthrough that will be fully exploited on PreClinLeish through testing in Leishmania murine infection models to advance the status of these molecules to bona fide leads. PreClinLeish will also go further beyond the state of the art by addressing the potential of other phosphomimetic cores (Figure 2). PreClinLeish aims to be a transforming force in Leishmania drug development, thus we will also exploit the potential of NAA, these are molecules with huge potential for drug development and through a collaboration with Ioannis Papanastasiou we will be able to evaluate a highly promising chemically focused library of molecules that is ready to test (Table 1). Finally, we will perform a screening of a~5000 molecules from the ECBPL to identify new anti-Leishmanial hits. These 3 drug development efforts constitute the core of the research developed in PreClinLeish. Considering this the main aim is clear: To deliver a pre-clinical level lead molecule Several other main goals will also be associated to PreClinLeish: To identify at least 1 new lead molecule for Leishmaniasis To identify new anti-Leishmanial hits for drug development To clarify the potential of Heterocyclic Miltefosine Phosphomimetics in Leishmania drug development To clarify the potential of Nifurtimox–Adamantane adducts in Leishmania drug development To increase awareness of CanL, One Health and Leishmaniasis Secondary goals that are to be addressed To generate information related to the mechanism of action of selected promising leads/hits and MLT. Ultimately, PreClineLeish seeks to advance CanL drug development and to deliver the bases for what would be the first drug of restricted veterinary use for Leishmaniasis.