Screening and evaluation of therapeutic candidates with vascular protective effects in zebrafish models of diabetic retinopathy.

We evaluated therapeutic peptide candidates for diabetic retinopathy (DR) using a zebrafish model. Three peptides, designed from a type II collagen-derived sequence, were evaluated for toxicity and vascular protective effects. Peptide 1 demonstrated favorable physicochemical stability, low toxicity (> 90% survival), and vascular protective activity. In contrast, Peptides 2 and 3 showed increased toxicity and morphological abnormalities at higher concentrations, limiting their potential utility. In a hyperglycemia-induced zebrafish DR model, Peptide 1 (100-200 µg/ml) reduced retinal vessel thickness with efficacy comparable to aflibercept. Molecular analysis by RT-PCR indicated that Peptide 1 suppressed vascular endothelial growth factor (VEGF) expression and enhanced Tie2 and Angiopoietin-1 (Ang-1) expression, suggesting a role in vascular stabilization. These findings establish zebrafish as a cost-effective and rapid screening platform for early-stage DR drug discovery. These findings support zebrafish as a cost-effective platform for early-stage diabetic retinopathy drug discovery and highlight Peptide 1 as a promising candidate for non-proliferative DR, providing a rationale for further optimization and mechanistic studies toward clinical translation.