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

光以其高时空分辨率控制生物系统的能力是无与伦比的。它具有非侵入性和远程操作，可逆性，速度快，以及容易调制所涉及的能量（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经成为一个非常有趣和迅速扩展的活动领域，从靶点验证到新治疗方式的确定，应用范围广泛。原则上，利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。虽然很少有研究将所谓的光开关结合到protac中，但关于最有效的设计仍然存在许多问题，而且这种方法尚未得到广泛应用。通过利用Fuchter团队的尖端光开关设计，我们建议进一步发展可光开关PROTACs （photac）的概念。开发的PHOTAC系统将用于揭示主要促炎细胞因子（IL1B）信号传导的基本方面，IL1B驱动多种疾病的炎症病理，包括痛风、类风湿性关节炎、神经退行性疾病、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