Engineered ligand-based VEGFR antagonists with increased receptor binding affinity more effectively inhibit angiogenesis.

ABSTRACT: Pathologic angiogenesis is mediated by the coordinated action of the vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling axis, along with crosstalk contributed by other receptors, notably α_vβ₃ integrin. We build on earlier work demonstrating that point mutations can be introduced into the homodimeric VEGF ligand to convert it into an antagonist through disruption of binding to one copy of VEGFR2. This inhibitor has limited potency, however, due to loss of avidity effects from bivalent VEGFR2 binding. Here, we used yeast surface display to engineer a variant with VEGFR2 binding affinity approximately 40-fold higher than the parental antagonist, and 14-fold higher than the natural bivalent VEGF ligand. Increased VEG

SUBMITTER: Kapur S 

PROVIDER: S-EPMC5412928 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature