Inhibition of CXCR4-Induced Angiogenesis to Block Choroidal Neovascularization and Restore Retinal Function in Age-Related Macular Degeneration by In Silico-Selected Small Molecules.
TL;DR
Computational and experimental data demonstrate that BPRCX807 disrupts CXCR4 receptor interactions and suppresses angiogenic factor expression via inhibition of the CXCR4/p-AKT signaling pathway, representing a promising therapeutic approach for wet-AMD.
Abstract
The chemokine receptor CXCR4 has been recognized as a pivotal mediator of cytokine-driven angiogenesis. Wet age-related macular degeneration (wet-AMD) is characterized by choroidal neovascularization (CNV) leading to vision loss. However, the current anti-VEGF therapy remains limited by recurrent CNV in refractory wet-AMD. Herein we developed small-molecule inhibitors targeting CXCR4-mediated neovascularization in wet-AMD. Employing computational molecular docking simulations for candidate screening, BPRCX807 exhibited superior binding affinity as a CXCR4 antagonist relative to other compounds tested. A laser-induced wet-AMD murine model was established, demonstrating subretinal CNV and upregulation of proteins implicated in CXCR4 signaling and angiogenesis. Retinal structural alterations and CNV-progression were monitored via real-time fluorescein angiography and optical coherence tomography (OCT), revealing that BPRCX807 treatment significantly attenuated angiogenesis compared to conventional anti-VEGF therapy. Retinal safety evaluation further indicated that BPRCX807 administration did not induce detectable retinal toxicity or structural abnormalities. Ex vivo choroid sprouting assays corroborated the reduction of vascular leakage and CNV-formation by BPRCX807. The visual-functional electroretinographic evaluations indicated that, while anti-VEGF agents produced modest functional improvements, BPRCX807 achieved superior restoration of retinal visual function. Notably, bioinformatic analyses supported that inhibition of CXCR4 signaling effectively suppressed VEGF-driven and cytokine-mediated angiogenic pathways. Finally, biomolecular simulations combined with predictive signaling-pathway analyses suggested that BPRCX807 modulates multiple VEGF-regulatory signaling cascades, thereby enhancing its inhibitory effects on VEGF expression and downstream angiogenesis. Collectively, these computational and experimental data demonstrate that BPRCX807 disrupts CXCR4 receptor interactions and suppresses angiogenic factor expression via inhibition of the CXCR4/p-AKT signaling pathway, representing a promising therapeutic approach for wet-AMD.