About Targeting a unique mRNA decapping enzyme for trypanosomatid infectious disease drug discovery, PhD - at Faculty of Science, Charles University

Kinetoplastids encode no homologues of canonical decapping enzymes. Instead, we identified the ApaH-like phosphatase ALPH1 acting as essential mRNA decapping enzyme in trypanosomes. We have characterized the enzyme, belonging to a family absent from mammalian systems, both biochemically and in the cellular context, with the conclusion that ALPH1 is meeting key criteria of a robust drug target.

With this target in hand, it is now possible to conduct a screening campaign to identify inhibitors with potential as highly selective next generation drugs. Thus, to build upon this breakthrough, we have assembled a team combining expertise in first stage drug discovery (Charles University in Prague), trypanosome biology (University of Wuerzburg), and structural biology of mRNA interacting proteins (University of Warsaw).

We will identify specific inhibitors of ALPH1 activity by high-throughput compound library screens followed by assessment of validated hit compounds for potency in trypanosome culture and Leishmania intramacrophage assays. In parallel, collaborators will subject these inhibitors to in situ decapping assays and structural characterisation of ALPH1 co-structures guiding rational design for compoud derivatisation. Ultimately, we aim to develop these compounds into preclinical candidate drugs for sleeping sickness, the leishmaniases and Chagas disease and to harness their potential as chemical biology tools.

Five relevant publications of the research group:

Kramer S, Karolak NK, Odenwald J, Gabiatti B, Casta

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