摘要
合成大环化合物的发展代表朝向新的蛋白结合或其已知在癌症中的信令以及在细胞分裂周期的调节中发挥关键的生物作用的蛋白质-蛋白质相互作用(PPI)抑制剂的识别的有效的方法。结构性调查确定了“热循环”共用同一机制--主要是与PPIs有关。大部分PPIs通过大型平面发生;目前,这些蛋白复合物被认为通过传统药物发现的方法无药可治,因为小分子的识别抑制这些靶标往往是无法达到的。 典型的大环大小是500-2000Da,有12元,甚至更多的环结构:他们不服从利平斯基规则,但是它们的性质为作为治疗药物提供了许多例子如红霉素(抗生素)、环孢菌素(免疫抑制剂)、生长抑素(激素)。 基于肽的大环化合物具有参与PPIs直接模仿次级结构的优点,它们的药理学应用与引导肽的潜在改善有关,在效力,选择性,稳定性和细胞渗透方面。 环肽着有希望的相关性提示开发用于环化的新合成方法:通常采用生物技术方法以及环肽快速和几乎定量的选择性反应。此外,拟肽大环化不同的合成策略实际上是可用的,基于替代肽键或NCL(天然化学结扎)方法。 本文侧重于环肽制备的最常用方法和过去十年间有趣的应用。
关键词: 蛋白质 - 蛋白质相互作用(PPI),大环化合物,环肽
Current Medicinal Chemistry
Title:Targeting “Undruggable” Proteins: Design of Synthetic Cyclopeptides
Volume: 23 Issue: 8
Author(s): Anna Russo, Carmela Aiello, Paolo Grieco and Daniela Marasco
Affiliation:
关键词: 蛋白质 - 蛋白质相互作用(PPI),大环化合物,环肽
摘要: The development of synthetic macrocycles represents a powerful approach toward the identification of new protein binders or inhibitors of Protein-Protein Interactions (PPI) which are known to play key biological roles in cancer signaling as well as in the regulation of cell division cycle. Structural investigations led to identify “hot loops” sharing common motifs that are mainly involved in PPIs. Most PPIs occur through large and flat surfaces; currently these protein complexes are defined as “undruggable” by conventional drug-discovery approaches, since the identification of small molecules to inhibit these targets is often unreachable.
Typically macrocycles are 500-2000 Da in size, having 12-membered, or more, ring architecture: they do not obey the Lipinski’s rule but, for them nature offers many examples as therapeutic agents such as erythromycin (antibiotic), cyclosporin (immunosuppressant) and somatostatin (hormone).
Peptide-based macrocycles offer the advantages of directly mimicking secondary structures involved in PPIs and their pharmacological application is related to the potential improvement of lead peptides in terms of potency, selectivity, stability and cell permeation.
The promising relevance of cyclopeptides prompted to develop new synthetic methods for cyclization: often biotechnological approaches as well as regioselective reactions have been employed to cyclize peptides rapidly and nearly quantitatively. Moreover, different synthetic strategies in peptidomimetics’ macrocyclization are actually available based on surrogate peptide bonds or NCL (Native Chemical Ligation) methods.
In this review we focus on the most common methods for the preparation of cyclopeptides and interesting applications of the last decade.
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Cite this article as:
Anna Russo, Carmela Aiello, Paolo Grieco and Daniela Marasco , Targeting “Undruggable” Proteins: Design of Synthetic Cyclopeptides, Current Medicinal Chemistry 2016; 23 (8) . https://dx.doi.org/10.2174/0929867323666160112122540
DOI https://dx.doi.org/10.2174/0929867323666160112122540 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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