Phosphopyruvate Hydratase Identified as Promising Drug Target for Chagas Disease and Leishmaniasis
Scientists have identified phosphopyruvate hydratase (PPH) as a viable drug target in kinetoplastid parasites and found that a natural compound called hinokinin shows antiparasitic activity against both Trypanosoma cruzi and Leishmania donovani. The study combined computational proteome mining, AI-based structural modeling, and laboratory experiments to validate the target and screen candidate compounds. The findings are significant because current treatments for Chagas disease and leishmaniasis are toxic and have limited efficacy, and this work offers a new cross-species therapeutic scaffold.
A new study published on bioRxiv presents an integrative drug discovery strategy targeting phosphopyruvate hydratase (PPH), an enzyme essential to the metabolism of kinetoplastid parasites including Trypanosoma cruzi, the causative agent of Chagas disease, and Leishmania donovani, which causes visceral leishmaniasis. Researchers used functional enrichment and druggability analyses to select PPH as a candidate, noting its essential metabolic role and low similarity to human homologs, which reduces the risk of off-target toxicity. AlphaFold-generated three-dimensional structural models of PPH were refined through molecular dynamics simulations to produce stable conformational ensembles suitable for virtual drug screening. Screening of the Latin American Natural Products Database (LANaPDB) identified aptosimon as a top-ranked candidate, with simulations suggesting it may bind PPH in modes distinct from the enzyme's natural substrate. In laboratory assays, the structurally related lignan compound hinokinin demonstrated antiparasitic activity against intracellular T. cruzi amastigotes (IC50 = 3.52 µg/mL) and L. donovani promastigotes (IC50 = 13.06 µg/mL), supporting the broader relevance of this chemical class. The authors conclude that PPH is a structurally tractable and biologically relevant drug target, and that the aptosimon-related lignan chemotype warrants further biochemical validation studies.
What's missing
The study has several important limitations: the in vitro activity of hinokinin has not been confirmed to act specifically through PPH inhibition, meaning the mechanism of action remains unvalidated. No selectivity index data comparing antiparasitic activity to mammalian cell cytotoxicity is reported for hinokinin in this study. In vivo efficacy and pharmacokinetic data are absent. The structural models used for virtual screening are computationally derived rather than experimentally determined (e.g., by X-ray crystallography), introducing uncertainty into the binding mode predictions. The preprint has not yet undergone peer review.
What different sources said
- bioRxivCenter
From Proteome Mining to Structural Validation: Phosphopyruvate Hydratase as a Structurally Tractable Drug Target in Kinetoplastid Parasites
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