biostudies-literatureUnknown17(1)Zhang RFor targeted covalent protein modification at low-reactivity aspartates and glutamates, new methods are in high demand. We report a technique inspired by the HaloTag technology, which employs nucleophilic substitution at chloroalkane-functionalised ligands by a specific aspartate residue. Embedding of alkyl bromide warheads into non-covalent inhibitors enables covalent modification of a glutamate in the lipoprotein binding chaperone - phosphodiesterase of retinal rod subunit delta (PDEδ), which shuttles prenylated lipoproteins between cellular membranes and thereby mediates their activity. Its hydrophobic ligand-binding pocket contains p.E88 as the only accessible nucleophile for covalent targeting. We show that a covalent inhibitor, termed DeltaTag, overcomes limitations of non-covalent iNature communications1257https://www.ebi.ac.uk/biostudies/studies/S-EPMC12864978biostudies-literatureCovalent modification of a glutamic acid inspired by HaloTag technology.PMC12864978Gasper RLiu JWaldmann HKaschani FJanning PZhang RUnger AKaiser MfalseCovalent modification of a glutamic acid inspired by HaloTag technology.For targeted covalent protein modification at low-reactivity aspartates and glutamates, new methods are in high demand. We report a technique inspired by the HaloTag technology, which employs nucleophilic substitution at chloroalkane-functionalised ligands by a specific aspartate residue. Embedding of alkyl bromide warheads into non-covalent inhibitors enables covalent modification of a glutamate in the lipoprotein binding chaperone - phosphodiesterase of retinal rod subunit delta (PDEδ), which shuttles prenylated lipoproteins between cellular membranes and thereby mediates their activity. Its hydrophobic ligand-binding pocket contains p.E88 as the only accessible nucleophile for covalent targeting. We show that a covalent inhibitor, termed DeltaTag, overcomes limitations of non-covalent i2026-01-01T00:00:00Z2026 Jan2026-07-15T06:32:23.416Z2026-06-30T03:21:58.745ZS-EPMC128649784161770410.1038/s41467-026-68999-9