Nucleoside analogues against trypanosomatid parasites: phenotypic screening and mechanism-of-action

Mon15  Apr05:48pm(3 mins)
Poster
25
Where:
Renold C2
Speaker:
Mr Camila Santos

Authors

C Cardoso-Santos3; D Mabille4; F Hulpia1; I Roditi5; S Van Calenbergh1; M N Correia Soeiro2; L Maes4; G Caljon4
1 Ghent University, Belgium;  2 Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Brazil;  3 Instituto Oswaldo Cruz, Rio de Janeiro, Brazil;  4 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium;  5 University of Bern, Switzerland

Discussion

Chagas disease (CD), human African trypanosomiasis (HAT) and Leishmaniasis are three neglected tropical diseases with a large medical need caused by trypanosomatid parasites. No human vaccines are available and current drugs have significant drawbacks in terms of efficacy, toxicity or development of resistance, justifying the need for alternative chemotherapies. Given that trypanosomatids are purine auxotrophs, focused purine libraries can be a source of antiparasitic agents as described in literature for both T. cruzi and T. brucei. A new series of nucleoside analogues was evaluated in vitro against a panel of trypanosomatid species, revealing four highly active candidates against T. cruzi (IC50 50-200 nM). In vivo proof-of-concept in an acute T. cruzi mouse infection model was already obtained for one particular compound (Hulpia et al, J. Med. Chem., 2018, PMID: 30234983). Surprisingly, one of the four compounds showed a broad anti-trypanosomatid potency, with nanomolar activity against T. brucei (IC50 < 0.5 µM) and promising activity against Leishmania infantum (IC50 2 µM) without cytotoxicity against murine primary macrophages or human fibroblasts (CC50 > 64 µM). This compound proved to be metabolically stable in the presence of rodent and human liver microsomes, which warrants further in vivo evaluation in the various trypanosomatid infection models and mechanismof-action (MOA) studies. Cross-resistance studies revealed a contribution of adenosine kinase (ADKIN) in the MoA whereas compound uptake is independent of the P2 adenosine transporter (AT1). A genome-wide T. brucei RNA interference (RNAi) library is currently being used to further scrutinize in an unbiased fashion the MoA of this potent anti-trypanosomatid nucleoside analogue.

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