| Full text | |
| 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: | 17/00674-2 - Estudos cristalográficos da TbG6PDH e de mutantes da TcG6PDH e complexos com inibidores |
| Grantee: | Amanda Gonçalves Eufrásio |
| Support Opportunities: | Scholarships in Brazil - Technical Training Program - Technical Training |
| 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 |