手性识别是生物体内最基本的分子识别模式，深入研究手性识别过程及规律，对不同镜像异构体的手性效应与功能发现具有重要意义。阿片类药物作为一类可穿透血脑屏障的小分子，具有典型的手性识别作用，天然阿片类药物为(-)-构型，可选择性识别人体内的GPCR受体。而人工合成的(+)-构型的阿片类化合物无法激活GPCR受体。TLR4是目前为止研究最为广泛，也是TLR家族最重要的蛋白之一。TLR4信号通路的激活与抑制必须受到严格的调控，以保持免疫系统的稳定。本项目拟在前期二价阿片类化合物可以手性识别TLR4的研究基础上，设计并合成不同刚性、柔性和光调控linker的多价阿片类化合物，构建手性分子库。系统研究多价阿片类手性分子结构与TLR4的手性效应与功能，明确对映体的生物活性差别。深入发掘立体选择性机制，发展新的手性TLR4的抑制剂。为神经疼痛和成瘾戒断等中枢神经相关疾病的手性药物设计奠定基础。

Chiral recognition is the most basic molecular recognition mode in living organisms. In-depth study of chiral recognition process and regularity is of great significance for the discovery of chiral effect and function of different enantiomer. Opioids, as a class of small molecules that can penetrate the blood-brain barrier, have typical property of chiral recognition. The natural opioids, which can selectively recognize endogenous classical G Protein-Coupled Receptors and lead to analgesia, addiction, etc., are (-)-configuration. However, the synthesized (+)-configuration opioids do not active the GPCR receptors. Toll-like receptor (TLR) 4 is the best studied by far and one of the most important proteins in the TLR family. Activation and inhibition of the TLR4 signaling pathway must be accurately regulated to maintain the stability of immune system. In this project, a multivalent opioid chiral molecular library will be constructed by connecting opioid molecular scaffold with rigid, flexible and light-regulated linkers, based on the previous study of bivalent opioid compounds. The chiral effects and functions of multivalent opioid chiral compounds targeting TLR4 will be studied systematically and the bioactivity difference of enantiomers will be clarified. This project will provide new ideas for drug design with high specificity and chirality to treat neurological diseases such as neuropathic pain and addiction withdrawal.