连接器
泛素连接酶
合理设计
化学
泛素
DNA连接酶
蛋白质水解
蛋白质工程
融合蛋白
组合化学
生物物理学
生物化学
纳米技术
计算生物学
计算机科学
材料科学
生物
酶
重组DNA
操作系统
基因
作者
Almaz Zagidullin,Vasili Miluykov,Albert A. Rizvanov,Emil Bulatov
标识
DOI:10.37349/etat.2020.00023
摘要
Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC properties, modulate binding kinetics and substantially impacts the potency and selectivity. In this review, the authors briefly discuss the recent findings in PROTAC design approaches with focus on the linker. For each PROTAC such linker parameters as chemical nature, length, hydrophilicity and rigidity have to be optimized to achieve improved stability, bioavailability cell membrane permeability and suitable spatial orientation between the target POI and the E3 ubiquitin ligase. Thus rational linker design with respect to composition, length and attachment sites is essential for the development of potent PROTAC compounds. Computer-aided design and novel innovative linker strategies, such as PROTAC shortening, photo-switchable PROTACs, in-cell click-formed CLIPTACs, "click chemistry" approaches are also discussed in the review.
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