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Proteome integral solubility alteration (PISA) analysis of compound treated Haemonchus contortus

ABSTRACT: This study applied the proteome integral solubility alteration (PISA) assay to infer molecular targets and protein–ligand interactions of candidate nematocidal compound in Haemonchus contortus. By monitoring compound-induced shifts in protein solubility across a temperature gradient, the analysis provided proteome-wide evidence of direct or indirect binding events in both adult female worms and in vitro-exsheathed third-stage larvae (xL3s). Protein extracts were prepared under standardised conditions, incubated with each test compound at ten times the LC₅₀, subjected to temperature challenges and then processed for tandem mass tag (TMT)-based quantitative proteomics using high-resolution LC-MS/MS. Resultant data sets were analysed via MaxQuant and Perseus, with protein identifications referenced to the annotated chromosome-scale genome of H. contortus Haecon-5.

INSTRUMENT(S):

ORGANISM(S): Haemonchus Contortus (barber Pole Worm)

TISSUE(S): Stem Cell, Whole Body

DISEASE(S): Parasitic Helminthiasis Infectious Disease

SUBMITTER: Tao Wang

LAB HEAD: Robin Beat Gasser

PROVIDER: PXD075263 | Pride | 2026-07-19

REPOSITORIES: Pride

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Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.

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Proteome integral solubility alteration (PISA) analysis of compound treated Haemonchus contortus

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