From waste to fuel for life: alanine as a flex metabolite in Trypanosoma cruzi

PAES, LS; PEREIRA, CA; MEYER-FERNANDES, JR; CRISPIM, M; DA SILVA, MS; ELIAS, MC; GIRARD, RM; ALENCAR, MB; PAVANI, RS; SILBER, ARIEL

Caxambu

Congreso; XXXIV Meeting of the Brazilian Society of Protozoology; 2018

Brazilian Society of Protozoology (SBPz)

Little is known about what pathways or proteins are responsible for Trypanosoma cruzi intracellulardevelopment in mammalian cell. We have identified a small molecule capable of interfering with T.cruzi intracellular development, causing inhibition of parasite replication without affecting parasite orhost cell viability. The functional characterization of the compound activity showed that: (i) thephenotype of intracellular development arrest was not restricted to a host cell type; (ii) the compoundwas able to inhibit the replication of different T. cruzi strains (Y, Sylvio X10/1 and CL Brener strain);(iii) the phenotype of arrest was reversible upon compound removal, once the parasite from that pointgrows normally concluding its intracellular cycle by differentiation to trypomastigotes; (iv) thecompound did not show cytotoxicity for distinct host cells (U2OS, LLC-MK2, NRK-52E and BHK-51)for up to 200 μM for 48 h, being highly selective for the parasite; (v) the molecule also is able to inducearrest in the epimastigote form of T. cruzi without loss of viability up to 96 h, but displayed a dosedependentcidal activity against bloodstream forms of Trypanosoma brucei and promastigote formsof Leishmania donovani; and (vi) the compound interfered with T. cruzi cell cycle, arresting most ofthe cell population at G0/G1. Altogether, these results suggest that this compound acts via a regulatorof cell cycle that can specifically cause arrest in T. cruzi and not in other trypanosomatids ormammalian cells. Future experiments will focus on target deconvolution to uncover the parasiteproteins related to the phenotype studied.