Poly-Dha Sequences\nas <i>Pro</i>-polypeptides:\nAn Original Mechanistic Postulate Leads to the Discovery of a Long-Acting\nVasodilator KU04212

The construction of polypeptides was revolutionized by\nMerrifield’s\nsolid-phase synthesis more than half a century ago. Herein, we explore\na completely different approach to making peptides. We test an original\nmechanistic postulate wherein a single peptide made entirely of dehydroalanine\n(Dha) residues can give rise to regio- and stereodefined peptides\nby iterative conjugate addition of one- or two-electron nucleophiles.\nEach nucleophile appends a unique amino acid side chain to the peptide\nbackbone. We show that side chain addition is not random. Side chains\nare added in one of two ways, in an electrophilicity-gated fashion\n(most cases) or in a substrate-directed manner, depending on the first\nnucleophile used in the synthesis. One peptide made in this series,\nKU04212, a <i>first-in-class</i> polyazole peptide, was\nfound to reduce vascular length density (−17%; <i>p</i> < 0.05) and increase vessel diameter (124%; <i>p</i> < 0.001) in healthy day 6 chick embryos at 24 h post-single dose.\nIt also rescued 75% of the embryos administered a 32-fold lethal dose\nof ischemia-inducing CoCl<sub>2</sub> after 12 h and 12.5% of the\nembryos after 24 h. In comparison to three mechanistically distinct\nvasodilators, e.g., isosorbide mononitrate, amlodipine besylate, and\nprazosin, only KU04212 showed long-acting effects <i>in vivo</i>, making it an enticing lead for the treatment of ischemic disorders.