3c828477817aa3dd9d98448627efb2d5 pmc_33445756.pdf 2eb38daa34a02be840c75ca44dc84336ea6744b8 pmc_33445756.pdf e7fd338991ec7f595393e65edf007e8c9b86dbf3aaa4a3d382f5946c72693e2b pmc_33445756.pdf Title: Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds Subject: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 mol L-1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. Keywords: Trypanosoma cruzi; Chagas disease; metabolism drugs; phenotypic assays; cytotoxicity assays; chronic in vivo model; dorsomorphin; 17-DMAG Author: Nieves Martinez-Peinado, Clara Martori, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Joaquim Gascon, Jordi Alberola, Maria-Jesus Pinazo, Alheli Rodriguez-Cortes and Julio Alonso-Padilla Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jan 12 12:28:39 2021 CET ModDate: Tue Jan 12 16:07:06 2021 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2947535 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HSNIKI+VnURWPalladioL Type 1 Custom yes yes no 10 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 15 0 ALFWWE+URWPalladioL-Ital Type 1 Custom yes yes 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Builtin yes yes no 261 0 UZKIAN+CMEX10 Type 1 Builtin yes yes no 275 0 RFLZJB+CMR10 Type 1 Builtin yes yes no 279 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:35:14 CEST RepresentationInformation: pmc_33445756.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:08:34 CEST Size: 2947535 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 563 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Anti-T. cruzi Activity Destination: subsection.2.1 Item: Title: Identification of Compounds with Specific Activity against the Parasite Destination: subsection.2.2 Item: Title: Anti-Amastigote Specific Activity of 17-DMAG Destination: subsection.2.3 Item: Title: Hsp90 Is the Target of 17-DMAG Destination: subsection.2.4 Item: Title: In Vivo Anti-T. cruzi Activity of 17-DMAG in a Mouse Model of Chronic Infection Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Collection of Compounds/Drugs Destination: subsection.4.1 Item: Title: Host Cells Cultures Destination: subsection.4.2 Item: Title: Culture of T. cruzi Parasites Destination: subsection.4.3 Item: Title: Assay to Detect T. cruzi Growth Inhibition in 96-Well Plates Destination: subsection.4.4 Item: Title: Cell Toxicity Assays Destination: subsection.4.5 Item: Title: In Silico Study of 17-DMAG Binding to Hsp90/83 N-Terminal Domains Destination: subsection.4.6 Item: Title: T. cruzi Chronic In Vivo Assay Destination: subsection.4.7 Item: Title: Data Analysis Destination: subsection.4.8 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds Author: Nieves Martinez-Peinado, Clara Martori, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Joaquim Gascon, Jordi Alberola, Maria-Jesus Pinazo, Alheli Rodriguez-Cortes and Julio Alonso-Padilla Subject: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 mol L-1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages. 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