呼吸道合胞病毒（RSV）是除甲流外最常见的呼吸道感染病毒，目前唯一被FDA批准用于治疗RSV感染的小分子药物利巴韦林，毒副作用大，且疗效尚有争议。本课题组长期从事基于岭南中草药的抗病毒活性成分研究，发现部分双咖啡酸类化合物显示出优于利巴韦林的抗RSV活性。作用机理研究表明，双咖啡酰奎宁酸甲酯可在RSV与宿主细胞膜融合前，作用于RSV囊膜上的融合蛋白（pre-fusion F蛋白），并首次发现其机理可能是通过抑制pre-fusion F蛋白中融合肽的释放，进而干扰F蛋白变构。但该类化合物稳定性差，其抗病毒活性还有很大的提高空间。基于以上工作基础，本课题拟以双咖啡酰奎宁酸甲酯为先导物，依据药核相似性及生物电子等排原理，设计合成系列双咖啡酸衍生物，并对其抗RSV活性及作用机制进行深入研究，以期获得高效、低毒、作用机制明确的小分子F蛋白抑制剂，为开发新型抗RSV药物提供先导物和科学依据。

Respiratory syncytial virus (RSV) is one of the most common respiratory infective viruses. Ribavirin is a broad-spectrum antiviral small drug approved by the FDA for the treatment of severe lower respiratory tract RSV infections in the high risks of hospitalized infants and young children. However, the application of ribavirin is limited by its high cytotoxicity and controversial antiviral efficacy. Our previous study showed that some dicaffeic acid derivatives, which were isolated from the medicinal herbs traditionally used in southern China, exhibited more potent anti-RSV activity than ribavirin. Structure-activity relationship (SAR) analysis by 3D-QSAR revealed that caffeoyl group is the active group for the anti-RSV activity of these compounds. The mechanistic study demonstrated that dicaffeoylquinic acid methyl ester can interact with RSV pro-fusion F protein. The compound can block the interaction of F(ecto) protein, the ectodomain of RSV-F protein, with the cellular membrane, and then inhibit viral fusion during RSV entry, leading to the inhibition of viral gene expression and infection. Therefore, caffeic acid derivative is a new type of RSV-F protein inhibitor and worth of further study. In this project, we will design and synthesize the molecular structures of caffeic acid derivatives on the basis of pharmacophore similarity and bioisosterism, and obtain more efficacy RSV-F protein inhibitors, and further explore the mechanism of caffeic acid derivatives that can inhibit the interaction of F(ecto) protein with the cell membrane. This study will provide scientific support for the development of novel antiviral agents with high potency and low toxicity.