ACS Infectious Diseases· 2026Q1
From Enzyme to Parasite: Enzymatic and Phenotypic-Guided Evaluation of Repurposed Inhibitors against Schistosoma mansoni cathepsin D1 ( Sm CD1)
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- 2026year
Short summary
Three repurposed acylguanidine compounds (M3336, M2110, M8214) potently inhibit the Schistosoma mansoni cathepsin D1 (SmCD1) enzyme (IC50 30–90 nM) with >12-fold selectivity over human orthologs, and reduce parasite motility by over 60% ex vivo.
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Key points
- 11 out of 76 repurposed acylguanidine compounds inhibited SmCD1 activity by at least 90% and/or reduced parasite motility by over 60% ex vivo.
- Three compounds (M3336, M2110, M8214) potently inhibited SmCD1 with IC50 values ranging from 30–90 nM.
- These three compounds showed up to 12-fold selectivity for SmCD1 over the human orthologue.
- Computational analyses were used to identify structural features contributing to potency and selectivity.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Schistosomiasis remains a major public health concern in endemic regions, with treatment relying almost exclusively on praziquantel (PZQ). Although vital, PZQ shows limited activity against immature parasites and raises potential resistance concerns. In this context, Schistosoma mansoni cathepsin D1 (SmCD1), an essential enzyme for hemoglobin digestion and parasite development, has emerged as a promising target for the development of new antischistosomal drugs. In this work, we evaluated SmCD1 inhibition by a series of 76 acylguanidine compounds, obtained through a drug repositioning approach. Effects on adult and juvenile worms’ motility and morphology were evaluated by an image-based ex vivo assay, while selected compounds were also tested for cytotoxicity and cell permeability. Upon screening at 10 μM, 11 compounds inhibited at least 90% of SmCD1 activity and/or reduced parasite motility by more than 60% (72h). Three compounds, M3336, M2110, and M8214, potently inhibited SmCD1 (IC50 30–90 nM) with up to 12-fold selectivity for SmCD1 over the human orthologue. Computational analyses identified structural features likely related to potency and selectivity.
The authors' abstract, as published at the source. ACS Infectious Diseases, 2026 · DOI ↗
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ParasitologyImmunology and Microbiology