biostudies-literatureUnknownLucero BNIAID NIH HHSTreatment of schistosomiasis, a prevalent neglected tropical disease, relies precariously on a single drug. The discovery and development of alternative anti-schistosomal small molecules most often relies on phenotypic (whole-organism) screening, whereas target- or "protein-first"-based discovery options are hampered by a paucity of genetic interrogation strategies and a complex biology. Here, we demonstrate the application of photoaffinity labeling (PAL) as a chemical biology strategy to probe protein target-ligand interactions in the schistosome. Using a triazolopyrimidine (TPD) probe that binds tubulin, we established a PAL workflow with living <i>Schistosoma mansoni</i> worms. The probe elicited deleterious phenotypic responses consistent with the TPD series and, upon UV light activatibioRxiv : the preprint server for biology2025.10.04.680471https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632543biostudies-literaturePhotoaffinity labeling of protein targets in a complex metazoan: proof-of-concept using a probe for &lt;i&gt;Schistosoma mansoni&lt;/i&gt; tubulin.PMC12632543T32 AI007036R21 AI156554Bufano MYao YBrancale ABallatore CBrunden KRAlle TFrancisco KRLucero BCaffrey CRfalsePhotoaffinity labeling of protein targets in a complex metazoan: proof-of-concept using a probe for &lt;i&gt;Schistosoma mansoni&lt;/i&gt; tubulin.Treatment of schistosomiasis, a prevalent neglected tropical disease, relies precariously on a single drug. The discovery and development of alternative anti-schistosomal small molecules most often relies on phenotypic (whole-organism) screening, whereas target- or "protein-first"-based discovery options are hampered by a paucity of genetic interrogation strategies and a complex biology. Here, we demonstrate the application of photoaffinity labeling (PAL) as a chemical biology strategy to probe protein target-ligand interactions in the schistosome. Using a triazolopyrimidine (TPD) probe that binds tubulin, we established a PAL workflow with living <i>Schistosoma mansoni</i> worms. The probe elicited deleterious phenotypic responses consistent with the TPD series and, upon UV light activati2025-01-01T00:00:00Z2025 Oct2026-06-14T03:18:05.389Z2026-06-14T03:09:06.869ZS-EPMC126325434127909810.1101/2025.10.04.680471