{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:05:38Z","timestamp":1789650338658,"version":"4.0.0"},"reference-count":22,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Peptide Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Two complementary series of novel tryptophan\u2010derived dipeptides (Trp\u2010X and X\u2010Trp) were designed and synthesized to systematically evaluate how backbone sequence inversion alters chemical accessibility and in\u00a0vitro antineoplastic profiles against a human solid tumor cell line panel (A549, HeLa, MIA PaCa\u20102, SW1573, T\u201047D, and WiDr). Reversing the peptide connectivity revealed prominent sequence\u2010dependent chemical reactivities and biological variations. Steric repulsion at the \u03b2\u2010carbon limited basic hydrolysis during X\u2010Trp precursor assembly, whereas the Trp\u2010X series allowed straightforward chemical couplings. Phenotypic screening demonstrated that the Trp\u2010X configuration is biologically superior to the X\u2010Trp layout. The conformationally restricted L\u2010proline conjugate (Trp\u2010Pro) emerged as the lead architecture, exhibiting consistent, single\u2010digit sub\u2010micromolar growth inhibition across all histotypes (GI\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.36\u20132.06\u2009\u03bcM) and effectively outperforming clinical standards cisplatin and 5\u2010fluorouracil in resistant models. Interestingly, an inversion of structure\u2013activity relationships was observed in the reverse series, where specific residues like L\u2010phenylglycine and L\u2010tyrosine experienced a prominent rescue of potency upon sequence relocation. These results confirm that the antiproliferative profile of these peptidomimetics is strictly dictated by a highly directional, sequence\u2010specific molecular topology rather than aggregate lipophilicity alone.\n                  <\/jats:p>","DOI":"10.1002\/psc.70128","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:25:54Z","timestamp":1789608354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sequence Inversion Dictates the Antiproliferative Activity of Bidirectional Tryptophan\u2010Containing Dipeptide Libraries"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0495-8577","authenticated-orcid":false,"given":"J. Benamer","family":"D\u00edaz","sequence":"first","affiliation":[{"name":"BioLab, Instituto Universitario de Bio\u2010Org\u00e1nica Antonio Gonz\u00e1lez Universidad de La Laguna  La Laguna Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8985-4632","authenticated-orcid":false,"given":"Adam N.","family":"Khan","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio\u2010Org\u00e1nica Antonio Gonz\u00e1lez Universidad de La Laguna  La Laguna Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-5194","authenticated-orcid":false,"given":"Aday","family":"Gonz\u00e1lez\u2010Bakker","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio\u2010Org\u00e1nica Antonio Gonz\u00e1lez Universidad de La Laguna  La Laguna Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6268-6552","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Padr\u00f3n","sequence":"additional","affiliation":[{"name":"BioLab, Instituto Universitario de Bio\u2010Org\u00e1nica Antonio Gonz\u00e1lez Universidad de La Laguna  La Laguna 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