适体
生物医学
共价键
生物物理学
DNA
生物
纳米技术
组合化学
化学
材料科学
生物化学
生物信息学
分子生物学
有机化学
作者
Fang Zhou,Peng Wang,Jianghuai Chen,Zhijia Zhu,Youshan Li,Sujuan Wang,Shanchao Wu,Yingyu Sima,Ting Fu,Weihong Tan,Zilong Zhao
摘要
Abstract Aptamers’ vast conformation ensemble consisting of interconverting substates severely impairs their performance and applications in biomedicine. Therefore, developing new chemistries stabilizing aptamer conformation and exploring the conformation–performance relationship are highly desired. Herein, we developed an 8-methoxypsoralen-based photochemically covalent lock to stabilize aptamer conformation via crosslinking the inter-stranded thymine nucleotides at TpA sites. Systematical studies and molecular dynamics simulations were performed to explore the conformation–performance relationship of aptamers, revealing that conformation-stabilized aptamers displayed better ability to bind targets, adapt to physiological environment, resist macrophage uptake, prolong circulation half-life, accumulate in and penetrate into tumor than their counterparts. As expected, conformation-stabilized aptamers efficiently improved the therapeutic efficacy of aptamer-drug conjugation on tumor-bearing mice. Collectively, our study has developed a general, simple and economic strategy to stabilize aptamer conformation and shed light on the conformation–performance relationship of aptamers, laying a basis for promoting their basic researches and applications in biomedicine.
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