posted on 2021-07-19, 17:36authored byGustavo
F. Mercaldi, Amanda G. Eufrásio, Americo T. Ranzani, Jessica do Nascimento Faria, Sabrina G. R. Mota, Michelle Fagundes, Marjorie Bruder, Artur T. Cordeiro
Chagas
disease, an infectious condition caused by Trypanosoma
cruzi, lacks treatment with drugs with desired efficacy and
safety profiles. To address this unmet medical need, a set of trypanocidal
compounds were identified through a large multicenter phenotypic-screening
initiative and assembled in the GSK Chagas Box. In the present work,
we report the screening of the Chagas Box against T. cruzi malic enzymes (MEs) and the identification of three potent inhibitors
of its cytosolic isoform (TcMEc). One of these compounds, TCMDC-143108
(1), came out as a nanomolar inhibitor of TcMEc, and
14 new derivatives were synthesized and tested for target inhibition
and efficacy against the parasite. Moreover, we determined the crystallographic
structures of TcMEc in complex with TCMDC-143108 (1)
and six derivatives, revealing the allosteric inhibition site and
the determinants of specificity. Our findings connect phenotypic hits
from the Chagas Box to a relevant metabolic target in the parasite,
providing data to foster new structure–activity guided hit
optimization initiatives.