Loktev Anastasia, Haberkorn Uwe, Mier Walter
Department of Nuclear Medicine, Heidelberg University Hospital, INF 400, 69120 Heidelberg. Germany.
Curr Med Chem. 2017;24(20):2141-2155. doi: 10.2174/0929867324666170316120304.
The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development. In recent years, miniproteins and multicyclic peptides have become the preferred ligands expressed by these libraries. Due to their favorable pharmacokinetics and the ease of their synthesis, peptidic ligands overcome disadvantages of antibody derived therapeutics. Peptides that are structurally defined by a rigid scaffold are ideally suited for the use in display techniques. These molecules feature high stability and excellent affinities while offering the opportunity to randomize partial sequences to be used as binding sites. Structurization of the peptide scaffold can be achieved by different approaches, of which cyclization is one of the most commonly used. The favored cyclization strategies are based on amide or disulfide bridging and the use of synthetic braces or chemical linkers. The use of multicyclic peptides allows the simultaneous presentation of several different binding loops. Semisynthetic approaches enable the introduction of unnatural amino acids, increasing the diversity of the resulting peptide libraries. Given that, miniprotein scaffolds offer a wide range of potential applications and facilitate efficient screening of novel high-affinity ligands to be used in precise diagnosis and highly efficient cancer therapy.
传统细胞毒性药物缺乏特异性，这促使人们研发对肿瘤特异性蛋白具有高选择性的抗癌药物。表皮生长因子受体（EGFR）或人表皮生长因子受体2（Her2）等靶点结构的揭示，推动了新型疗法的针对性研发，并极大地促进了肿瘤治疗的进展。可通过噬菌体展示、酵母表面展示、核糖体展示和mRNA展示等技术来鉴定肿瘤特异性高亲和力配体。这些技术能够筛选庞大的文库，从而为合理药物研发提供了一种有价值的替代方法。近年来，微蛋白和多环肽已成为这些文库所表达的首选配体。由于其良好的药代动力学特性以及易于合成，肽类配体克服了抗体衍生疗法的缺点。由刚性支架结构定义的肽非常适合用于展示技术。这些分子具有高稳定性和出色的亲和力，同时提供了将部分序列随机化作为结合位点的机会。肽支架的结构化可通过不同方法实现，其中环化是最常用的方法之一。常用的环化策略基于酰胺或二硫键桥接以及使用合成支架或化学连接剂。多环肽的使用允许同时呈现几个不同的结合环。半合成方法能够引入非天然氨基酸，增加所得肽文库的多样性。鉴于此，微蛋白支架具有广泛的潜在应用，并有助于高效筛选用于精确诊断和高效癌症治疗的新型高亲和力配体。
