Monobodies as tool biologics for accelerating target validation and druggable site discovery.
Monobodies as tool biologics for accelerating target validation and druggable site discovery.
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DOI：
10.1039/d1md00188d
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发表时间：
2021-11-17
影响因子：
4.1
通讯作者：
Koide S
中科院分区：
文献类型：
--
作者：
Akkapeddi P;Teng KW;Koide S
尽管加大了投资和技术进步，但新药批准并没有按比例增加。药物批准率低，特别是新靶点的批准率低，与早期阶段靶点验证不足有关。因此，仍然强烈需要有效的目标验证技术。在这里，我们回顾了合成结合蛋白作为药物靶点验证工具的使用，重点是几个先进的合成结合蛋白平台中的单体平台。使用蛋白质工程技术，可以针对具有挑战性的靶标（例如KRAS突变体）快速开发具有高亲和力和高选择性的单体。它们具有与功能位点结合的强烈倾向，因此可以作为药物样分子，并且它们可以作为构建bio-PROTAC的靶向配体。遗传编码的单抗体是用于验证细胞内靶标的有效“工具生物制剂”。它们促进结晶并有助于揭示单体-靶界面的原子结构，这可以为药物设计提供信息。通过案例研究，我们说明了单体技术在加速靶标验证和小分子药物发现方面的潜力。快速开发具有精确选择性和高效力的靶结合蛋白有助于验证具有挑战性的细胞内靶点。
Despite increased investment and technological advancement, new drug approvals have not proportionally increased. Low drug approval rates, particularly for new targets, are linked to insufficient target validation at early stages. Thus, there remains a strong need for effective target validation techniques. Here, we review the use of synthetic binding proteins as tools for drug target validation, with focus on the monobody platform among several advanced synthetic binding protein platforms. Monobodies with high affinity and high selectivity can be rapidly developed against challenging targets, such as KRAS mutants, using protein engineering technologies. They have strong tendency to bind to functional sites and thus serve as drug-like molecules, and they can serve as targeting ligands for constructing bio-PROTACs. Genetically encoded monobodies are effective “tool biologics” for validating intracellular targets. They promote crystallization and help reveal the atomic structures of the monobody-target interface, which can inform drug design. Using case studies, we illustrate the potential of the monobody technology in accelerating target validation and small-molecule drug discovery. Rapid development of target-binding proteins with exquisite selectivity and high potency helps validate challenging intracellular targets.
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影响因子：
15.9
作者：
Al-Khodor S;Price CT;Kalia A;Abu Kwaik Y
通讯作者：
Abu Kwaik Y
影响因子：
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