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Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

Authors :
Li, Yuanyuan
Guo, Shu'ai
Wu, Xinjing
Wan, Jiale
Guan, Yonghui
Luo, Chenghui
Chen, Qin
Jiang, Hongyu
Lin, Haiyan
Qian, Hai
Shi, Wei
Fan, Wen
Source :
Bioorganic Chemistry. Jun2024, Vol. 147, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

[Display omitted] • Based on the binding pattern of the N -terminal region of CCR3 protein to CCL11, a series of cyclic peptides targeting the C C motif chemokine receptor 3 (CCR3) have been designed. • Optimized compound IB-2 may have a protective effect on photoreceptor cells. • Optimized compound IB-2 demonstrated good anti-angiogenic activity in vitro experiments. • In vivo experiments, Optimized compound IB-2 demonstrated promising therapeutic efficacy. The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting C C motif chemokine receptor 3 (CCR3). Based on the binding mode of the N -terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00452068
Volume :
147
Database :
Academic Search Index
Journal :
Bioorganic Chemistry
Publication Type :
Academic Journal
Accession number :
177222314
Full Text :
https://doi.org/10.1016/j.bioorg.2024.107405