文章：

致癌蛋白界面：小分子，大挑战

Oncogenic protein interfaces: small molecules, big challenges

原文发布日期：2014-03-13

DOI: 10.1038/nrc3690

类型: Review Article

开放获取: 否

要点：

1. More than 300,000 interaction pairs have already been identified in the human genome; therefore, modulating protein–protein interactions (PPIs) has a huge potential for therapeutic intervention in cancer.
2. The refinement of existing bioassay techniques and the development of new ones, together with the identification and exploitation of unexpected aspects of PPI surfaces has led to more than 12 small-molecule PPI modulators making it to the clinic in recent years.
3. Advances in the structural and biological understanding of the PPI to be modulated are shaping the compound libraries being used for PPI screening; for example, three-dimensional shape diversity, chirality and pharmacokinetic properties are now included in the library design.
4. Improvements in data handling, robotics and miniaturization of assay technology has allowed increasing numbers of compounds to be evaluated against a given protein target using high-throughput screening (HTS) methods.
5. The availability of cheap computational power has led to the routine use of virtual screening in the discovery of small-molecule PPI modulators, either as a stand-alone method to identify potential hits or as a prelude to HTS. Active compounds that are identified from the virtual screening process then undergo a traditional medicinal chemistry optimization process.
6. Sensitive methods such as protein-based or ligand-based NMR, X-ray diffraction and surface plasmon resonance allow the use of fragments of low affinity and specificity to be used for the discovery and development of small-molecule PPI modulators.
7. The therapeutic class of biologicals, which includes antibodies, peptides and aptamers, generally has high target specificity and potency. Biologicals are particularly useful for PPI modulation, as they can be readily tuned to bind to a large variety of protein surfaces and are often used as a starting point for PPI drug discovery programmes.

要点翻译：

1. 人类基因组中已识别超过30万对相互作用关系，因此调控蛋白质-蛋白质相互作用（PPIs）在癌症治疗干预方面具有巨大潜力。
2. 现有生物检测技术的改进与新方法的开发，结合对PPI表面意外特性的发掘与利用，已促使近年来超过12种小分子PPI调节剂进入临床阶段。
3. 对靶向PPI结构和生物学认知的进展正在重塑用于PPI筛选的化合物库设计：例如当前库构建已纳入三维形状多样性、手性及药代动力学特性等参数。
4. 数据处理技术、自动化操作系统和检测技术微型化的提升，使得通过高通量筛选方法评估特定蛋白靶标的化合物数量大幅增加。
5. 廉价计算资源的普及推动虚拟筛选成为小分子PPI调节剂发现的常规手段——既可独立识别潜在活性化合物，也可作为高通量筛选的前置步骤。
6. 通过虚拟筛选发现的活性化合物将进入传统药物化学优化流程。基于蛋白质或配体的核磁共振、X射线衍射和表面等离子共振等灵敏检测方法，使得低亲和力、低特异性的分子片段也能用于小分子PPI调节剂的研发。
7. 生物制剂（包括抗体、多肽和适配体）这类治疗药物通常具有高靶标特异性和强效性。它们能通过精确调整与多种蛋白质表面结合，在PPI调控中展现独特优势，因此常作为PPI药物研发计划的起点。

英文摘要：

Historically, targeting protein–protein interactions with small molecules was not thought possible because the corresponding interfaces were considered mostly flat and featureless and therefore 'undruggable'. Instead, such interactions were targeted with larger molecules, such as peptides and antibodies. However, the past decade has seen encouraging breakthroughs through the refinement of existing techniques and the development of new ones, together with the identification and exploitation of unexpected aspects of protein–protein interaction surfaces. In this Review, we describe some of the latest techniques to discover modulators of protein–protein interactions and how current drug discovery approaches have been adapted to successfully target these interfaces.

摘要翻译： 

历史上，人们曾认为用小分子靶向蛋白-蛋白相互作用是不可能的，因为对应的界面大多平坦且无特征，因此被视为“不可成药”。相反，这类相互作用通常用较大的分子（如肽和抗体）来靶向。然而，过去十年中，通过现有技术的优化和新技术的开发，以及对蛋白-蛋白相互作用表面意外特征的识别与利用，取得了令人鼓舞的突破。在本综述中，我们介绍了发现蛋白-蛋白相互作用调节剂的最新技术，以及当前药物发现方法如何被改进以成功靶向这些界面。

原文链接：

Oncogenic protein interfaces: small molecules, big challenges