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, Castañeda Londoño PA, Zavřelová A, Freire ER, Almeida KS, Braune S, Moreira C, Eder A, Goos C, Field M, Carrington M, Holetz F, Górna MW, Zoltner M. A unique mRNA decapping complex in trypanosomes. Nucleic Acids Res. 2023 Aug 11;51(14):7520-7540.

Ženíšková K, Mach J, Arbon D, Štursa J, Werner L, Zoltner M, Sutak R. The 4-Aminomethylphenoxy-Benzoxaborole AN3057 as a Potential Treatment Option for Primary Amoebic Meningoencephalitis. Antimicrob Agents Chemother. 2023 Feb 16;67(2):e0150622.

Marcelino TP, Fala AM, da Silva MM, Souza-Melo N, Malvezzi AM, Klippel AH, Zoltner M, Padilla-Mejia N, Kosto S, Field MC, Burle-Caldas GA, Teixeira SMR, Couñago RM, Massirer KB, Schenkman S. Identification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation. J Biol Chem. 2023 Jul;299(7):104857.

Singh V, Hada RS, Jain R, Vashistha M, Kumari G, Singh S, Sharma N, Bansal M, Poonam, Zoltner M, Caffrey CR, Rathi B, Singh S. Designing and development of phthalimides as potent anti-tubulin hybrid molecules against malaria. Eur J Med Chem. 2022 Sep 5;239:114534.

Zhang N, Zoltner M, Leung KF, Scullion P, Hutchinson S, Del Pino RC, Vincent IM, Zhang YK, Freund YR, Alley MRK, Jacobs RT, Read KD, Barrett MP, Horn D, Field MC. Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles. PLoS Pathog. 2018 Feb 9;14(2):e1006850.

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