Structural computational modeling of RNA aptamers.
Structural computational modeling of RNA aptamers.
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DOI：
10.1016/j.ymeth.2016.03.004
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发表时间：
2016-07-01
期刊：
影响因子：
--
通讯作者：
Giangrande PH
中科院分区：
文献类型：
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作者：
Xu X;Dickey DD;Chen SJ;Giangrande PH
RNA适体代表了一类新兴的生物制剂，可以很容易地适应个性化和精准医学。在过去的25年中，已经开发了几种具有期望的结合和功能特性的治疗适体，并在临床前研究中进行了评估。然而，对于大多数这些适体，其临床潜力尚未实现。这类新型生物制剂的临床应用的一个重大障碍是其二级和三级结构的信息有限。RNA结构的知识将极大地促进和加快翻译所需的选择后优化步骤，包括截短（以降低制造成本）、化学修饰（以增强稳定性和提高安全性）和化学缀合（以提高组合疗法的药物特性）。在这里，我们描述了一种结构计算建模方法，当耦合到一个标准的功能测定，可以用来确定关键序列和结构基序的RNA适体。我们应用这种方法能够截短前列腺特异性膜抗原（PSMA）的适体，具有很大的靶向治疗潜力，以前的截短尝试失败了。这种方法可以很容易地应用于优化其他具有治疗潜力的适体。
RNA aptamers represent an emerging class of biologics that can be easily adapted for personalized and precision medicine. Several therapeutic aptamers with desirable binding and functional properties have been developed and evaluated in preclinical studies over the past 25 years. However, for the majority of these aptamers, their clinical potential has yet to be realized. A significant hurdle to the clinical adoption of this novel class of biologicals is the limited information on their secondary and tertiary structure. Knowledge of the RNA’s structure would greatly facilitate and expedite the post-selection optimization steps required for translation, including truncation (to reduce costs of manufacturing), chemical modification (to enhance stability and improve safety) and chemical conjugation (to improve drug properties for combinatorial therapy). Here we describe a structural computational modeling methodology that when coupled to a standard functional assay, can be used to determine key sequence and structural motifs of an RNA aptamer. We applied this methodology to enable the truncation of an aptamer to prostate specific membrane antigen (PSMA) with great potential for targeted therapy that had failed previous truncation attempts. This methodology can be easily applied to optimize other aptamers with therapeutic potential.