Helix mimetics: Recent developments.
Helix mimetics: Recent developments.
复制标题
螺旋模拟物：最新进展。
DOI：
10.1016/j.pbiomolbio.2015.05.001
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发表时间：
2015
影响因子：
3.8
通讯作者：
Andrew J. Wilson
中科院分区：
文献类型：
--
作者：
Andrew J. Wilson
蛋白质-蛋白质相互作用（PPIs）抑制剂的开发代表了化学生物学和药物发现中具有挑战性的目标。PPI是有问题的目标，因为它们涉及大的表面，具有不太明确的特征和识别基序，这些特征和识别基序不太适合常规的实验和计算配体发现方法。α-受阻素介导的PPI代表了具有明确定义的界面的亚组，因此可能更适合开发通用配体发现方法。事实上，这在许多研究中得到证实，这些研究使用共价约束成螺旋构象的肽，导致无数生物物理和细胞性质的改善。然而，期望具有小分子替代物：螺旋模拟物（蛋白质模拟物）是一种通用的小分子支架，其以类似的空间取向投射官能团，以便模拟介导PPI的螺旋的关键氨基酸侧链的呈递。螺旋模拟物的第一个真正的例子是在十多年前描述的，但是这种方法还没有被详细阐述到与限制肽类似的关注程度。这篇综述探讨了小分子α-螺旋模拟物领域的最新重大进展，并对成功案例、该方法的潜在局限性和未来发展领域进行了重要概述。
The development of protein–protein interaction (PPIs) inhibitors represents a challenging goal in chemical biology and drug discovery. PPIs are problematic targets because they involve large surfaces with less well defined features and recognition motifs that are less amenable to conventional experimental and computational ligand discovery methodologies. α-Helix mediated PPIs represent a sub group with a clearly defined interface and thus may be more amenable to the development of generic ligand discovery methods. Indeed, this is borne out in numerous studies using peptides covalently constrained into a helical conformation resulting in improvement of myriad biophysical and cellular properties. It is however desirable to have small molecule alternatives: a helix mimetic (proteomimetic) is a generic small molecule scaffold that projects functional groups in a similar spatial orientation so as to mimic the presentation of key amino acid side chains from the helix that mediates the PPI. The first true example of a helix mimetic was described over a decade ago however this approach has not yet been elaborated to the extent that it receives similar levels of attention to constrained peptides. This review explores recent significant developments in the area of small molecule α-helix mimetics and provides a critical overview of success stories, potential limitations of the approach, and areas for future development.
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影响因子：
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