HPLW's primary function revolves around its ability to interact with cellular targets, potentially involved in immune modulation or protein-binding activities. Many synthetic peptides, such as HPLW, are designed to study interactions between peptides and proteins, which is vital for understanding molecular signaling and immune responses. VEGF receptors have been the target of intense research to develop molecules that inhibit or stimulate angiogenesis. HPLW, KQLLWIRSGDRPWYTS, a 17-mer ?-hairpin peptide based on the ?-hairpin sequence 87–100 of PlGF. Interestingly, HPLW adopts the expected fold in pure water, targets VEGF receptors, and shows in vitro and in vivo VEGF-like activity. It is one of the few peptides with pro-angiogenic activity reported to date. This peptide could find application in the area of therapeutic angiogenesis. The structure-based design of a novel VEGF receptor-binding bioactive peptide was reported. The peptide KQLLWIRSGDRPWYTS was modeled on the PlGF ?-hairpin region 87–100 and stabilized by an aromatic hydrophobic cluster. The designed peptide assumes a well-folded ?-hairpin conformation in an aqueous solution with high structural similarity to the natural sequence. The NMR interaction analysis revealed that the peptide binds to VEGFR1D2, highlighting at the molecular level the residues involved in the interaction. These residues correspond to receptor residues involved in the PlGF hairpin recognition. In vitro biological characterization showed that it is a bioactive peptide with VEGF-like activity. Moreover, the peptide was able to induce angiogenesis in vivo. HPLW is one of the few peptides known with proangiogenic activity, making it a candidate for the development of a novel peptide-based drug for medical applications in therapeutic angiogenesis. | 