A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

Abstract

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

MicroRNA‑203a‑3p suppresses endothelial cell proliferation and invasion, and promotes apoptosis in hemangioma by inactivating the VEGF‑mediated PI3K/AKT pathway

“…The VEGF family consists of cytokines known to be angiogenic factors that participate in blood vessel formation and lymphangiogenesis (30). VEGFA is the main member of this family of proteins, which has been revealed to regulate cell proliferation, apoptosis and invasion (11)(12)(13)31,32). In particular, VEGFC has also been reported to impact the progression of hemangioma (22).…”

Decoding the synergistic potential of MAZ‐51 and zingerone as therapy for melanoma treatment in alignment with sustainable development goals

“…55 In mammals the VEGF family consists of VEGF-A, B, C and D, placental growth factor (PIGF) as well as the homologs that are expressed in Orf viruses including VEGF-E and VEGF-F expressed in snake venom. [55][56][57] Alternative splicing and proteolytic processing yield various isoforms of the proteins. 55,56 VEGFs induce signalling through their receptor tyrosine kinases, VEGFR 1,2 and 3 with ligand binding yielding receptor homo or heterodimerisation, conformational changes and auto or transphosphorylation of tyrosine residues, ultimately activating signalling cascades that promote cell proliferation, survival and migration.…”

“…The differentiation of endothelial cells during the embryonic period, postnatal vasculature development and sprouting of vessels during pathology is reliant on VEGFs and their corresponding receptors (VEGFRs) 54 . VEGFs are structurally related angiogenic and lymphangiogenic factors that are constituents of the PDGF subgroup of the growth factor cystine knot group 55 . In mammals the VEGF family consists of VEGF‐A, B, C and D, placental growth factor (PIGF) as well as the homologs that are expressed in Orf viruses including VEGF‐E and VEGF‐F expressed in snake venom 55–57 .…”

Dimer Peptide Ligands of Vascular Endothelial Growth Factor: Optimizing Linker Length for High Affinity and Antiangiogenic Activity

“…We describe here a dimerization strategy to maintain high binding affinity to VEGF through an avidity effect while keeping the size of the peptide-based ligand small. Several peptides have been described as ligands of VEGF. , The 19-amino acid VEGF binding peptide v114 was identified by phage display, and improvements of its structure have since been achieved. − We shortened this peptide to 15 amino acids and introduced a helix-stabilizing lactam bridge . The resulting peptide has an affinity of 38 nM for VEGF and has a molecular weight of 2 kDa.…”

“…Several peptides have been described as ligands of VEGF. 12,13 The 19-amino acid VEGF binding peptide v114 was identified by phage display, 14 and improvements of its structure have since been achieved. 15−17 We shortened this peptide to 15 amino acids 18 and introduced a helix-stabilizing lactam bridge.…”