Next generation PHOTACS: A light switchable system for enhanced spatial and temporal precision in targeted protein degradation

光在控制生物系统方面具有无与伦比的能力，具有高空间和时间分辨率。它具有非侵入性和远程作用，可逆性，速度和所涉及的能量的容易调制（通过使用不同的波长/颜色）的优点。通过双功能PROTAC小分子控制蛋白质降解已成为一个非常有趣且快速扩展的活性领域，具有一系列应用，从靶标验证到新治疗方式的鉴定。原则上，使用光以高空间和时间精度“关闭”和“打开”这种PROTAC的能力提供了更多的机会。虽然已经出现了少量的研究，将所谓的光开关纳入PROTAC，但对于最有效的设计仍然存在许多问题，并且该方法尚未得到广泛应用。通过利用Fuchter集团的尖端光电开关设计，我们建议进一步发展光开关PROTAC（PHOTAC）的概念。开发的PHOTAC系统将被用来解开主要促炎细胞因子（IL 1B）信号传导的基本方面，IL 1B驱动几种疾病的炎症病理学，包括痛风、类风湿性关节炎、神经变性、糖尿病和几种遗传性发热综合征

Light is unsurpassed in its ability to control biological systems with high spatial and temporal resolution. It has the advantages of noninvasive and remote action, reversibility, speed, and facile modulation of the energies involved (through use of different wavelengths/colours). The control of protein degradation by bifunctional PROTAC small molecules has become a highly interesting and rapidly expanding area of activity with a range of applications, from target validation to the identification of new therapeutic modalities. In principle, the ability to turn such PROTACs 'off' and 'on' with high spatial and temporal precision using light offers yet more opportunities. While a low number of studies have emerged incorporating so-called photoswitches into PROTACs, many questions remain over the most effective designs and the approach is yet to have been applied broadly. By leveraging cutting-edge photoswitch designs from the Fuchter group, we propose to further develop the concept of photoswitchable PROTACs (PHOTACs). The developed PHOTAC system will be employed to unpick fundamental aspects of signalling of a major proinflammatory cytokine (IL1B), which drives inflammatory pathology in several diseases, including gout, rheumatoid arthritis, neurodegeneration, diabetes, and several hereditary fever syndromes