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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box

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Author(s):
Mercaldi, Gustavo F. [1] ; Eufrasio, Amanda G. [1, 2] ; Ranzani, Americo T. [1, 2] ; Faria, Jessica do Nascimento [1] ; Mota, Sabrina G. R. [3, 1] ; Fagundes, Michelle [1] ; Bruder, Marjorie [1] ; Cordeiro, Artur T. [1, 2]
Total Authors: 8
Affiliation:
[1] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083970 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Fac Pharmaceut Sci, BR-13083871 Campinas, SP - Brazil
[3] Univ Estadual Campinas, Inst Biol, BR-13083970 Campinas, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: ACS INFECTIOUS DISEASES; v. 7, n. 8, p. 2455-2471, AUG 13 2021.
Web of Science Citations: 0
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 crystallo-graphic 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. (AU)

FAPESP's process: 15/03336-5 - Evaluating the malic enzyme as a target in the treatment of Chagas Disease
Grantee:Américo Tavares Ranzani
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 13/03983-5 - Functional and structural studies of the enzymes related to the NADPH production in trypanosomatids
Grantee:Artur Torres Cordeiro
Support Opportunities: Regular Research Grants
FAPESP's process: 14/15590-0 - Discovery of new Leishmania mexicana glucose-6-phosphate isomerase inhibitors.
Grantee:Sabrina Gondim Ribeiro Mota
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 18/22202-8 - Characterization of T. cruzi metabolic targets for the research of drug for Chagas Disease
Grantee:Artur Torres Cordeiro
Support Opportunities: Regular Research Grants
FAPESP's process: 16/19141-1 - Discovery of Non-Phosphorylated Glucose-6 Phosphate Isomerase Inhibitors
Grantee:Sabrina Gondim Ribeiro Mota
Support Opportunities: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 12/23682-7 - Structural characterization of malic enzyme of Trypanosoma cruzi and inhibitor discovery by a High-Throughput Screening assay.
Grantee:Américo Tavares Ranzani
Support Opportunities: Scholarships in Brazil - Doctorate