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Although a number of broad\u2010spectrum electrophilic, phosphotyrosine\u2010mimicking probes have been developed to covalently capture the catalytic site of these enzymes, there is still a high demand for PTP probes with high target selectivity that are accessible in a synthetically straightforward way. Unsaturated phosphorus (V) (P(V)) compounds have recently emerged as powerful cysteine\u2010selective bioconjugation reagents (P5\u2010labeling). Herein, we introduce ethynyl\u2010substituted aryl phosphonamidic and phosphonic acids as phosphotyrosine mimics, which serve as active\u2010site\u2010directed, covalent probes for tyrosine phosphatases. We show that these P(V) electrophiles can be readily incorporated into a peptide sequence, allowing proximity\u2010enabled reactivity and selective targeting of the catalytic cysteine residue of an interacting phosphatase, as exemplified for PTP1B, a protein tyrosine phosphatase that acts as a key negative regulator of insulin signaling. Both ethynyl phosphonamidic acid and ethynyl phosphonic acid show no reactivity towards nontarget cysteine residues, though the phosphonamidic acid probe was notably less reactive toward its intended target. Proteomics experiments in human cell lysates demonstrated that the phosphonic acid probe selectively enriches its interacting phosphatase in the human proteome. Our study highlights a versatile strategy to obtain remarkably precise peptide\u2010based PTP probes, thereby enabling the characterization of phosphatase interactions with high specificity.<\/jats:p>","DOI":"10.1002\/anie.202521902","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:46:52Z","timestamp":1770187612000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unsaturated Phosphorus Electrophiles to Probe Protein Tyrosine Phosphatases"],"prefix":"10.1002","volume":"65","author":[{"given":"Eleftheria","family":"Poulou","sequence":"first","affiliation":[{"name":"Department of Chemical Biology Leibniz\u2010Forschungsinstitut F\u00fcr Molekulare Pharmakologie (FMP) Berlin Germany"},{"name":"Department of Chemistry Humboldt Universit\u00e4t zu Berlin  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Ruwolt","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Leibniz\u2010Forschungsinstitut F\u00fcr Molekulare Pharmakologie (FMP) Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian E.","family":"Stieger","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Leibniz\u2010Forschungsinstitut F\u00fcr Molekulare Pharmakologie (FMP) Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Kemnitz\u2010Hassanin","sequence":"additional","affiliation":[{"name":"Department of Chemical Biology Leibniz\u2010Forschungsinstitut F\u00fcr Molekulare Pharmakologie (FMP) Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7457-4742","authenticated-orcid":false,"given":"Christian P. 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