Identification and functional analysis of a novel potent anti-angiogenesis peptide SAIF-B2 derived from shark...

Marine-derived bioactive molecules represent promising candidates for lead drug development. Structural optimisation of these lead drugs significantly enhances their suitability as drugs, setting the framework for large-scale manufacturing. We previously identified shark-derived angiogenesis inhibition factor (SAIF), a 33 amino acid peptide from shark cartilage, which has anti-angiogenic activity but has inadequate in vivo stability, thereby limiting clinical translation. In this study, we employed a computational molecular docking-guided truncation strategy to optimise and screen SAIF-B2, a truncated 20 amino acid peptide. SAIF-B2 improved plasma proteolytic stability by 67 % while maintaining strong affinity for vascular endothelial growth factor receptor 2 and vascular endothelial growth factor A. Functionally, SAIF-B2 decreased HUVEC proliferation, migration and tube formation in a dose-dependent manner, resulting in G1/S phase cell cycle arrest. SAIF-B2 markedly suppressed neovascularisation in the chick chorioallantoic membrane assay and zebrafish models. Transcriptomic analysis revealed its anti-angiogenic mechanism, which involves the suppression of VEGF, MAPK, and PI3K-AKT signalling pathways. Notably, SAIF-B2 exhibited potent anti-tumour effects in a hepatocellular carcinoma model and effectively inhibited pathological corneal neovascularisation. These findings establish SAIF-B2 as a superior marine-derived anti-angiogenic peptide with enhanced stability (67 % improvement), smaller molecular weight, and lower production costs than those of its parent molecule. This multi-target therapeutic agent shows significant potential for treating angiogenesis-driven pathologies, including malignancies and macular degeneration, thereby warranting further preclinical development.