血管生成
血管内皮生长因子
细胞生物学
癌细胞
癌症研究
生物信息学
化学
转录因子
HIF1A型
生物
分子生物学
癌症
生物化学
基因
血管内皮生长因子受体
遗传学
作者
Nilanjan Banerjee,Laboni Roy,Suman Panda,Tanaya Roychowdhury,Subhrangsu Chatterjee
摘要
ABSTRACT Vascular endothelial growth factor‐A (VEGF‐A) is a growth factor and pluripotent cytokine that promotes angiogenesis in cancer cells, transitioning to an angiogenic phenotype. The binding of VEGF‐A protein to VEGF receptors (VEGFR‐1 and VEGFR‐2) initiates a cascade of events that stimulates angiogenesis by facilitating the migration and enhancing the permeability of endothelial cells. The proximal promoter of the VEGF gene encompasses a 36‐base pair region (from −85 to −50) that can form a stable G‐quadruplex (G4) structure in specific conditions. The activity of the VEGF promoter is reliant on this structure. During cancer progression, the VEGF‐A G4 succumbs to cellular pressure and fails to maintain a stable structure. This shifts the balance to form a duplex structure, increasing the transcription rate. Earlier research has tried to develop small‐molecule ligands to target and stabilise G4, demonstrating the possibility of suppressing VEGF expression. However, they either lack specificity or toxic. Peptides, on the other hand, are significantly less studied as G4 binders. Here, we designed a peptide that successfully binds and stabilises the VEGF‐A G4 while reducing its gene expression. This further alters the expression fate of the VEGF‐A signalling cascade and blocks angiogenesis in cancer cells. We employed high‐resolution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation to elucidate the chemical details of G4‐peptide interaction. In addition, we used qPCR and western blot techniques to investigate the expression pattern of the molecules implicated in the VEGF‐A signalling cascade. The study explores the intricate relationship between peptides and quadruplex structures, revealing valuable insights that can improve the design of pharmacophores targeting the dynamic quadruplex structure. The results of our study are encouraging, opening possibilities for advancements in, the characterisation and optimisation of peptides as G‐quadruplex ligands in view of their potential therapeutic uses.
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