ArticlePLoS neglected tropical diseases2013
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.
Article in PLoS neglected tropical diseases, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 56 citations in OpenAlex.
- Hsp90 and associates shaping parasite biology.mSphere · 2025Review
- Article
- Is theMicroorganisms · 2023Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor.International journal of molecular sciences · 2022Article
- Review
- Article
- Cytosolic and Mitochondrial Hsp90 in Cytokinesis, Mitochondrial DNA Replication, and Drug Action in Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2021Article
- Article
- Anti-International journal of molecular sciences · 2021Article
- Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan ParasiteFrontiers in cell and developmental biology · 2021Article
- Discovery of small molecule inhibitors ofJournal of enzyme inhibition and medicinal chemistry · 2020Article
- Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites.International journal of molecular sciences · 2019Review
- A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90.Scientific reports · 2019Article
- Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus.Nature communications · 2019Article
- Predictive classification models and targets identification for betulin derivatives as Leishmania donovani inhibitors.Journal of cheminformatics · 2018Article
- Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2018Article
- Repurposing drugs to target the malaria parasite unfolding protein response.Scientific reports · 2018Article
- 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice.International journal for parasitology. Drugs and drug resistance · 2018Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.