Metabolic and conformational stabilization of a VEGF-mimetic beta-hairpin peptide by click-chemistry

: HPLW is a Vascular Endothelial Growth Factor (VEGF)-mimicking beta-hairpin peptide endowed of proangiogenic effect and showing valuable biomedical application in the proangiogenic therapy. However, the translational potential of HPLW is limited by its low metabolic stability, which would shorten the in vivo efficacy of the molecule. Here, we developed a peptide analog of HPLW, named HPLW2, that retains the structural and biological properties of the original peptide but features an impressive resistance to degradation by human serum proteases. HPLW2 was obtained by covalently modifying the chemical structure of the peptide with molecular tools known to impart protease resistance. Notably, the peptide was cyclized by installing an interstrand triazole bridge through Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. HPLW2 appears as a novel and promising drug candidate with potential biomedical application in the proangiogenic therapy as a low molecular weight drug, alternative to the use of VEGF. Our work points out the utility of the interstrand triazole bridge as effective chemical platform for the conformational and metabolic stabilization of beta-hairpin bioactive peptides.