Red-light modulated ortho-chloro azobenzene photoswitch for peptide stapling via aromatic substitution.
Red-light modulated ortho-chloro azobenzene photoswitch for peptide stapling via aromatic substitution.
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DOI：
10.1039/d3cb00176h
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发表时间：
2024-01-03
影响因子：
4.1
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使用光可切换接头的肽钉合的应用对于潜在的治疗应用已经获得了显著的兴趣。然而，许多现有的光开关方法仍然依赖于使用组织损伤和弱皮肤穿透UV光。在本文中，我们描述了一种四邻氯偶氮苯接头的开发，该接头成功地用于通过SNAr进行半胱氨酸选择性肽钉合。该接头有助于通过在红光照射下的反式至顺式异构化对肽结构进行精确的光控制。作为概念验证，我们将开发的肽钉合平台应用于修饰的PMI肽，靶向MDM 2/p53蛋白质-蛋白质相互作用（PPI）的抑制。通过竞争性荧光偏振对光可切换肽进行生物物理表征，显示反式和顺式异构体对人MDM 2的p53相互作用结构域的亲和力存在显着差异。值得注意的是，顺式异构体显示出>240倍的效力。据我们所知，这是报道的光可切换治疗肽的同种型之间结合亲和力的最高差异。总的来说，我们的研究结果表明，这种新型的光开关肽钉合系统通过可见光异构化与深层组织穿透红光的可调，选择性调制PPI的潜力。具有在可见光照射时触发结合亲和力的主要变化的能力的光可切换肽钉合物的开发和概念验证。
The application of peptide stapling using photoswitchable linkers has gained notable interest for potential therapeutic applications. However, many existing methodologies of photoswitching still rely on the use of tissue-damaging and weakly skin-penetrating UV light. Herein, we describe the development of a tetra-ortho-chloro azobenzene linker that was successfully used for cysteine-selective peptide stapling via SNAr. This linker facilitates precise photocontrol of peptide structure via trans to cis isomerisation under red light irradiation. As a proof-of-concept, we applied the developed peptide stapling platform to a modified PMI peptide, targeting the inhibition of MDM2/p53 protein–protein interaction (PPI). Biophysical characterisation of the photoswitchable peptide by competitive fluorescence polarisation showed a significant difference in affinity between the trans and cis isomer for the p53-interacting domain of the human MDM2. Remarkably, the cis isomer displayed a >240-fold higher potency. To the best of our knowledge, this is the highest reported difference in binding affinity between isoforms of a photoswitchable therapeutic peptide. Overall, our findings demonstrate the potential of this novel photoswitchable peptide stapling system for tuneable, selective modulation of PPIs via visible-light isomerisation with deeply-tissue penetrating red light. Development and proof-of-concept for a photoswitchable peptide staple with the ability to trigger a major change in binding affinity upon visible light irradiation.