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

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

  • Pharmacol Res. 2025 Dec:222:108042. doi: 10.1016/j.phrs.2025.108042.
Alberto Zani 1,  Antonella Bugatti 1,  Eleonora Maceroni 2,  Melissa Duheric 1,  Matteo Uggeri 3,  Ekta Manocha 1,  Marta Bertelli 1,  Michele d'Angelo 4,  Annamaria Cimini 4,  Francesca Caccuri 5,  Arnaldo Caruso 6
Affiliations

Affiliations

  • 1 Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
  • 2 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
  • 3 Lifescience Innovation Good Healthcare Technology-LIGHT s.c.ar.l, Brescia 25123, Italy.
  • 4 Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, PA, United States.
  • 5 Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Center for Advanced Medical and Pharmaceutical Research (CCAMF), George Emil Palade University of Medicine, Pharmacy, Science and Technology, Târgu Mures, Romania. Electronic address: [email protected].
  • 6 Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Center for Advanced Medical and Pharmaceutical Research (CCAMF), George Emil Palade University of Medicine, Pharmacy, Science and Technology, Târgu Mures, Romania. Electronic address: [email protected].
PMID: 41274394 DOI: 10.1016/j.phrs.2025.108042
Abstract

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.

Keywords

Akt phosphorylation; Diabetic retinopathy; HHV-6 U94 protein; angiogenesis; β-arrestin-1.

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