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In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)<jats:sup>1<\/jats:sup>-Xaa<jats:sup>2<\/jats:sup>-Xaa<jats:sup>3<\/jats:sup>-Arg<jats:sup>4<\/jats:sup> have been previously discovered. In the current work, we focused on Lys(Har)-Dap\/Dab-Pro-Arg sequence. The aim was to examine whether replacing C-terminal Arg with its homologs and mimetics would yield more stable yet still potent inhibitors. Upon considering the results of modelling and other factors, ten novel analogues with Xaa<jats:sup>4<\/jats:sup>\u2009=\u2009homoarginine (Har), 2-amino-4-guanidino-butyric acid (Agb), 2-amino-3-guanidino-propionic acid (Agp), citrulline (Cit), 4-aminomethyl-phenylalanine [Phe(4-CH<jats:sub>2<\/jats:sub>-NH<jats:sub>2<\/jats:sub>)] were designed, synthesized and evaluated. Two of the proposed modifications resulted in inhibitors with activity slightly lower [e.g. IC<jats:sub>50<\/jats:sub>\u2009=\u200914.3\u00a0\u03bcM for Lys(Har)-Dab-Pro-Har and IC<jats:sub>50<\/jats:sub>\u2009=\u200919.8\u00a0\u03bcM for Lys(Har)-Dab-Pro-Phe(4-CH<jats:sub>2<\/jats:sub>-NH<jats:sub>2<\/jats:sub>)] than the parent compounds [e.g. IC<jats:sub>50<\/jats:sub>\u2009=\u20094.7\u00a0\u03bcM for Lys(Har)-Dab-Pro-Arg]. What was a surprise to us, the proteolytic stability depended more on position two of the sequence than on position four. The Dab<jats:sup>2<\/jats:sup>-analogues exhibited half-life times beyond 60\u00a0h. Our results build up the knowledge on the structural requirements that effective VEGF-A<jats:sub>165<\/jats:sub>\/NRP-1 inhibitors should fulfil.<\/jats:p>","DOI":"10.1007\/s00726-024-03411-8","type":"journal-article","created":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T18:02:55Z","timestamp":1724522575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Peptidomimetic inhibitors of the VEGF-A165\/NRP-1 complex obtained by modification of the C-terminal arginine"],"prefix":"10.1007","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8909-4087","authenticated-orcid":false,"given":"Dagmara","family":"Tymecka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8654-580X","authenticated-orcid":false,"given":"Patrycja","family":"Redkiewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8364-7955","authenticated-orcid":false,"given":"Piotr F. 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