Stapled Peptides as Potential Therapeutics
Stapled Peptides as Potential Therapeutics
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DOI：
10.1002/9780470015902.a0028403
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
L. McDougall;A. Jamieson
中科院分区：
文献类型：
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作者：
L. McDougall;A. Jamieson
钉合肽是一类重要的构象受限的生物活性α-螺旋肽。它们已被广泛用作调节蛋白质-蛋白质相互作用（PPI）的化学探针，其中一种目前正在进行后期临床试验，作为肽类药物候选物。它们与浅蛋白质-蛋白质界面相互作用的能力，以前已被证明是具有挑战性的小分子靶向，导致它们被化学生物学和药物发现社区迅速吸收。钉合肽克服了限制肽作为治疗剂的使用的一些不期望的物理化学性质。它们通常表现出良好的结合亲和力和特异性，因为它们旨在从PPI界面准确复制α-螺旋识别基序。它们具有蛋白酶抗性，并且在某些情况下显示出良好的细胞渗透性。因此，钉合肽的开发通过验证困难的PPI作为治疗靶点并提供有希望的候选药物而导致了变革性转变。
Stapled peptides are an important class of conformationally constrained, bioactive α‐helical peptides. They have been used extensively as chemical probes for the regulation of protein–protein interactions (PPIs), with one currently progressing through late‐stage clinical trials as a peptide drug candidate. Their ability to interact with shallow protein–protein interfaces, which have previously proven to be challenging to target with small molecules, has led to their rapid uptake by the chemical biology and drug discovery communities. Stapled peptides overcome some of the undesirable physicochemical properties that limit the use of peptides as therapeutics. They generally exhibit good binding affinity and specificity as they aim to accurately reproduce the α‐helix recognition motif from a PPI interface. They are protease resistant and in some instances have shown good cell permeability. The development of stapled peptides has thus resulted in a transformative shift by validating difficult PPIs as therapeutic targets and providing promising drug candidates.