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Trypanosoma cruzi malic enzyme is the target for sulfonamide hits from the GSK Chagas Box

DOI: 10.1021/acsinfecdis.1c00231 DOI Help

Authors: Gustavo F. Mercaldi (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials) , Amanda G. Eufrásio (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials; University of Campinas) , Americo T. Ranzani (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials; University of Campinas) , Jessica Do Nascimento Faria (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials) , Sabrina G. R. Mota (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials) , Michelle Fagundes (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials) , Marjorie Bruder (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials) , Artur Cordeiro (Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials; University of Campinas)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 11088

Abstract: 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.

Journal Keywords: Trypanosoma cruzi; malic enzyme; sulfonamides; GSK Chagas Box; Tres Cantos anti-kinetoplastids set; target-inhibitor structure

Diamond Keywords: Chagas Disease; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: W01B-MX2 at Brazilian Synchrotron Light Laboratory (LNLS)

Added On: 20/07/2021 14:27

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Drug Discovery Infectious Diseases Structural biology Chemistry Biochemistry Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)