A broad-spectrum anti-angiogenic tetrapeptide regresses diabetic retinopathy through β-arrestin-1 binding and prevention of Akt phosphorylation

Proliferative diabetic retinopathy (DR) is characterized by neovascularization which can lead to neovascular glaucoma, retinal detachment and blindness. To date, the treatment of DR consists in the intravitreal injection of anti-VEGF antibody (Ab), the only drug currently approved for DR therapy. U94, the latency protein of the human herpesvirus type 6, is endowed with anti-angiogenic activity on human endothelial cells. Here, we identify the tetrapeptide KDKY as the U94 functional epitope. It displays a broad-spectrum anti-angiogenic activity by binding to the intracellular protein β-arrestin-1 and preventing Akt phosphorylation, thus impairing activation of the main pro-angiogenic pathway. A single intravitreal administration of the KDKY peptide showed therapeutic efficacy against DR in a streptozotocin-induced diabetes mouse model. The KDKY in vivo potency was similar to that exerted by anti-VEGF Ab. Overall, our data highlight the possible use of KDKY as a minimalist drug in developing promising new DR therapeutic strategies.