Anti-trypanosoma cruzi activity of metabolism modifier compounds

Nieves Martinez-Peinado, Clara Martori, Nuria Cortes-Serra, Julian Sherman, Ana Rodriguez, Joaquim Gascon, Jordi Alberola, Maria Jesus Pinazo, Alheli Rodriguez-Cortes*, Julio Alonso-Padilla

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

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 µmol 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.

Original languageAmerican English
Article number688
Pages (from-to)1-16
Number of pages16
JournalInternational Journal of Molecular Sciences
Volume22
Issue number2
DOIs
Publication statusPublished - 2 Jan 2021

Keywords

  • 17-DMAG
  • Chagas disease
  • Chronic in vivo model
  • Cytotoxicity assays
  • Dorsomorphin
  • Metabolism drugs
  • Phenotypic assays
  • Trypanosoma cruzi

Fingerprint Dive into the research topics of 'Anti-trypanosoma cruzi activity of metabolism modifier compounds'. Together they form a unique fingerprint.

Cite this