Gatto B, Palumbo M, Sissi C
University of Padova, Department of Pharmaceutical Sciences, Via Marzolo, 5 - 35131 Padova, Italy.
Curr Med Chem. 2009;16(10):1248-65. doi: 10.2174/092986709787846640.
Aptamers are short DNA- or RNA-based oligonucleotides selected from large combinatorial pools of sequences for their capacity to efficiently recognize targets ranging from small molecules to proteins or nucleic acid structures. Like antibodies, they exhibit high specificity and affinity for target binding. As a result, they may display effective interference in biological processes, which renders them not only valuable diagnostic tools, but also promising therapeutic agents. In fact, one aptamer that inhibits human VEGF already received approval for the treatment of age-related macular degeneration, while several others are undergoing clinical trials. Aptamers display a large number of structural arrangements, which accounts for their binding efficiency and selectivity for unrelated targets. Among several architectures, the G-quadruplex (G-4) is adopted by several aptamers, the most popular of which shows inhibitory properties against thrombin, a pharmacologically relevant protein. G-4 structures consist of planar arrays of four guanines, each guanine pairing with two neighbours by Hoogsteen bonding. Recent work shows that G-4 arrangement is highly polymorphic and therefore represents a large family of stable structures with a common overall fold, but with well differentiated recognition elements that allow prominent diversity to be explored. Conformational plasticity consents fine tuning of target recognition as obtained by aptamer selection. Here, we will review the present knowledge on aptamers based on the G-4 structures and assess their diagnostic and therapeutic potential as biotech drugs for the detection and treatment of severe pathologies including vascular, cancer and viral diseases.
适体是基于DNA或RNA的短寡核苷酸，从大量序列组合文库中筛选出来，因其能够有效识别从小分子到蛋白质或核酸结构等各种靶标。与抗体一样，它们对靶标结合表现出高特异性和亲和力。因此，它们可能在生物过程中发挥有效的干扰作用，这使其不仅成为有价值的诊断工具，而且还是有前景的治疗药物。事实上，一种抑制人血管内皮生长因子（VEGF）的适体已被批准用于治疗年龄相关性黄斑变性，其他几种也正在进行临床试验。适体呈现出大量的结构排列方式，这解释了它们对不相关靶标的结合效率和选择性。在几种结构中，几种适体采用了G-四链体（G-4）结构，其中最常见的一种对凝血酶（一种具有药理学相关性的蛋白质）具有抑制特性。G-4结构由四个鸟嘌呤的平面阵列组成，每个鸟嘌呤通过Hoogsteen键与两个相邻鸟嘌呤配对。最近的研究表明，G-4排列具有高度多态性，因此代表了一大类具有共同整体折叠的稳定结构，但具有差异明显的识别元件，从而可以探索显著的多样性。构象可塑性允许通过适体筛选对靶标识别进行微调。在这里，我们将综述基于G-4结构的适体的现有知识，并评估它们作为生物技术药物在检测和治疗包括血管疾病、癌症和病毒疾病在内的严重病症方面的诊断和治疗潜力。
