针对特定结构域的TRPV1离子通道调控分子的理性设计与验证

疼痛严重地影响人们的身心状态与生活质量，同时给社会带来极大的医疗开支负担。作为疼痛与外界伤害性刺激的感受器，细胞膜上的TRPV1离子通道是良好的镇痛药物靶点。然而，由于TRPV1通道也是人体内重要的高温感受器，所以单纯地降低该通道的活性将引起体温升高、温度感觉改变等副作用：故很多通过大规模筛选得出的TRPV1抑制剂在临床试验中纷纷失败。因此，如何在开发以TRPV1通道为靶点的镇痛药物中避免这些副作用就是一个亟待解决的科学问题。针对这个科学问题，本项目基于该通道的高分辨率三维结构，以数个特定结构域为靶标，采用“热点中心”策略，理性设计并验证针对TRPV1通道的多个蛋白质调控分子，使其发挥正向变构调节剂或者激活模式特异的抑制剂的作用。本项目将为以该通道为靶点的镇痛药物开发提供理论支持与先导分子。本项目采用的理性设计策略也将广泛适用于针对各种三维结构已知的蛋白质药物靶点的调控分子开发。

Pain is an unpleasant and stressful experience that adversely affects the wellbeing of people all over the globe and imposes a heavy social and economic burden. As a polymodal nociceptor, Transient Receptor Potential Vanilloid 1（TRPV1）ion channels are highly expressed in nociceptive afferent nerve terminal, which are activated to transduce pain signals. Therefore, TRPV1 channel is a validated target for analgesic drugs. However, since TRPV1 is also the sensor for noxious temperature in human, the first generation of TRPV1 inhibitors failed in clinical trials as analgesics because they caused severe side effects such as much elevated body temperature and changed acute heat sensation. To avoid such side effects, this study aims to rationally design with the hot-spot centric strategy and validate protein modulators of TRPV1 channel by targeting different domains of the channel. These modulators are expected to exert analgesic effect by working as positive allosteric modulators or modality-specific inhibitors. This study will lay the theoretical foundation and provide lead molecules to the development of novel analgesic drugs targeting TRPV1 channel. The hot-spot centric rational design method employed in this project is also broadly applicable to create modulators to any protein target when its three-dimensional structure is available.