β-Hairpin Peptide That Targets Vascular Endothelial Growth Factor (VEGF) Receptors

Abstract

VEGF receptors have been the target of intense research aimed to develop molecules able to inhibit or stimulate angiogenesis. Based on the x-ray structure of the complex placental growth factor-VEGF receptor 1 D2 , we designed a VEGF receptor-binding peptide reproducing the placental growth factor ␤-hairpin region Gln 87 -Val 100 that is involved in receptor recognition. A conformational analysis showed that the designed peptide adopts the expected fold in pure water. Moreover, a combination of NMR interaction analysis and cell binding studies were used to demonstrate that the peptide targets VEGF receptors. The VEGF receptor 1 D2 -interacting residues were characterized at the molecular level, and they correspond to the residues recognizing the placental growth factor sequence Gln -Val 100. Finally, the peptide biological activity was characterized in vitro and in vivo, and it showed a VEGF-like behavior. Indeed, the peptide activated VEGF-dependent intracellular pathways, induced endothelial cell proliferation and rescue from apoptosis, and promoted angiogenesis in vivo. This compound is one of the few peptides known with proangiogenic activity, which makes it a candidate for the development of a novel peptide-based drug for medical applications in therapeutic angiogenesis.

Deciphering RGDechi peptide‐α5β1 integrin interaction mode in isolated cell membranes

“…In the last years, we have characterized the structures and functions of peptides recognizing membrane receptors either in vitro and on cellular membranes . Recently, we have also investigated the use of isolated cellular membranes and provided significant advantages in the structural study of the RGDechi interaction with α v β 3 integrin .…”

Targeting kinase signaling pathways with constrained peptide scaffolds

“…Of the enzyme-linked receptors, receptor tyrosine kinases have received much attention as targets for the development of anti-proliferative, anti-metastatic, and anti-angiogenic compounds in cancer due to their roles in cell growth and motility (Regad, 2015). A variety of constrained peptides have been developed to target ligand-induced activation of receptor tyrosine kinases by blocking the receptor-binding surface of the ligand or by occluding the ligand-binding site of the receptor (Blaskovich, et al, 2000; De Rosa, et al, 2014; Diana, et al, 2011; Guardiola, et al, 2016; Lamberto, et al, 2014; Lamberto, et al, 2012; Murai, et al, 2003; Nakamura, et al, 2005; Tam, et al, 2009; Vicari, Foy, Liotta, & Kaumaya, 2011). By blocking ligand binding, the peptides can prevent the conformational change and dimerization that promotes kinase activation and subsequent tyrosine phosphorylation events (Figure 2).…”

“…Another receptor tyrosine kinase, vascular endothelial growth factor receptor (VEGFR), has roles in angiogenesis (Shibuya, 2013), and has become an attractive target for the development of anti-angiogenic peptides (De Rosa, et al, 2014; Diana, et al, 2011; Vicari, et al, 2011). A peptide mimicking a receptor-binding loop of vascular endothelial growth factor (VEGF) was developed to bind VEGFR-2 and block its activation in cancer (Vicari, et al, 2011).…”

“…Although no direct binding or inhibitory effect on VEGFR was reported, the peptides were capable of blocking downstream signaling events and decreasing VEGF-induced proliferation in cells. Interestingly, in the absence of the disulfide bond, the peptide was reported to have agonistic activity (Diana, et al, 2011), suggesting the importance of the disulfide cross-link for antagonistic activity.…”

Structural investigation of the VEGF receptor interaction with a helical antagonist peptide

“…Over the last several years, we reported the structural and biological properties of several VEGFR binder peptides designed on VEGF regions involved in VEGFR recognition such as the N‐terminal helix (residues 17–25) and the β ‐hairpin encompassing residues 79–92 .…”