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The viral protease NS2B\u2010NS3 is essential for the replication of Zika and other orthoflaviviruses, making it a target for antiviral drug development. Traditional discovery of competitive inhibitors has relied on substrate recognition sequences, typically yielding multibasic peptides. Herein, a de novo strategy is presented for identifying competitive inhibitors using peptide phage display in combination with Bi(III)\u2010mediated in\u2009situ formation of bicyclic peptides. In an initial screening, phages displaying a library of randomized peptide\u2010bismuth bicycles are eluted by interrupting the phage\u2010target interactions at low pH. This approach yields a small number of peptides biased toward the active site, characterized by dibasic motifs, but only one low\u2010ranking sequence shows modest inhibitory activity. To enhance specificity, a second screening campaign employs competitive phage elution using the dibasic boronate inhibitor CN\u2010714 that covalently binds to the catalytically active serine residue S135 of NS2B\u2010NS3. This strategy enriches a larger pool of competitive inhibitors sharing the characteristic dibasic substrate recognition motif. The most potent peptide\u2010bismuth bicycle identified and synthesized features a completely novel sequence, exhibits an inhibition constant of 3.9\u2009\u00b5M and displays remarkable proteolytic stability over 24\u2009h.<\/jats:p>","DOI":"10.1002\/cbic.202500674","type":"journal-article","created":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T14:02:32Z","timestamp":1762092152000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["De Novo Discovery of Bicyclic Competitive Inhibitors of Zika Virus Protease from Peptide\u2013Bismuth Phage Display Screening"],"prefix":"10.1002","volume":"26","author":[{"given":"Upamali","family":"Somathilake","sequence":"first","affiliation":[{"name":"Research School of Chemistry Australian National University  Canberra ACT 2601 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