Drug Repurposing of Octreotide as a Selective Apelin Receptor Antagonist Against Pathological Angiogenesis: Integrated Virtual Screening and Zebrafish Validation

Abstract

Purpose:

The apelin/APJ system represents a promising VEGF-independent therapeutic target for treating retinopathy of prematurity (ROP), given its selective upregulation in pathological retinal neovasculature. We aimed to identify clinically translatable APJ antagonists that suppress pathological neovascularization without VEGF-related side effects.

Methods:

We employed a hypoxia-induced zebrafish ROP model to recapitulate pathological neovascularization, combined with structure-based virtual screening of 2,506 FDA-approved drugs targeting the APJ receptor (PDB ID: 6KNM). Lead compounds were evaluated through in vitro angiogenesis assays (human umbilical vascular endothelial cells [HUVEC] tube formation, migration, and invasion) and in vivo efficacy testing.

Results:

Among 21 initial hits, octreotide (X-3) showed the most potent anti-angiogenic activity, with an IC₅₀ of 0.016 µM in HUVECs. Mechanistically, X-3 selectively downregulated APJ expression without altering VEGF/VEGFR levels. Functional assays confirmed its ability to suppress endothelial tube formation, migration, and invasion.

Conclusions:

Our findings identified octreotide as a novel APJ antagonism with high translational potential, offering a dual advantage—targeting pathological neovascularization while preserving physiological VEGF signaling. These findings support its repurposing as a precision therapy for ROP and other ocular neovascular disorders.