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Substituting non\u2010natural, aromatic amino acids in cyclic peptide motifs can improve the ability of such peptides to bind to their protein targets and can further prevent instability. Here, we appended our previously described synthetic head\u2010to\u2010tail cyclized peptide with naphthylalanine (Nap) or biphenylalanine (BiPhe) substitutions in one or two positions. Our first\u2010generation inhibitor targeted the protein\u2013protein interaction between von Willebrand factor and collagen, implicated in thrombosis linked to cardiovascular diseases. Through an unplanned modification, we omitted a glycine that usually aids the flexibility of ring closing. Using our previously developed fluorescently linked immunosorbent assay, we saw modest improvements for most of the Nap\u2010 or BiPhe\u2010substituted peptides, with the largest changes occurring with the no\u2010glycine compound, yielding an inhibitory concentration of 6.47\u2009\u03bcM. An array of stability was obtained for all of the peptides using protease degradation assays; however, every BiPhe\u2010 or Nap\u2010substituted peptide showed limited degradation over time. Through a \u201chappy accident,\u201d we discovered a new cyclic peptide scaffold, decreasing flexibility in our head\u2010to\u2010tail ring structure, paving the way for novel, potent, cyclic peptides with therapeutic value against thrombosis.<\/jats:p>","DOI":"10.1002\/cmdc.70457","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:02:05Z","timestamp":1787716925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Coalescence of a \u201cHappy Accident\u201d and an In Vitro Structure\u2013Activity Panel: Increasing the Potency of a Cyclic Peptide Inhibitor to Thrombosis Initiation"],"prefix":"10.1002","volume":"21","author":[{"given":"Gianna M.","family":"Barreto","sequence":"first","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4377-8568","authenticated-orcid":false,"given":"Breanna","family":"Wixted","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Kouba","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A.","family":"Riordan","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Tonks","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryley","family":"David","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis L.","family":"Oldfield","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7074-0764","authenticated-orcid":false,"given":"Austin","family":"Lisojo","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6775-6564","authenticated-orcid":false,"given":"Danielle A.","family":"Guarracino","sequence":"additional","affiliation":[{"name":"Department of Chemistry The College of New Jersey  Ewing New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"57","volume-title":"Scientific and Technological Thinking","author":"Dunbar K. 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