Zheng Youle, Song Yanbin, Feng Jin, Wen Defeng, Chang Mengyu, Song Mengping, Cao Hua, Ling Min, Yu Yixin, Tao Yanfei, Li Wentao, Wang Xu
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China; College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University; Hubei Hongshan Laboratory, Wuhan 430070, China.
Bioorg Chem. 2025 Aug;163:108637. doi: 10.1016/j.bioorg.2025.108637. Epub 2025 May 27.
Pigs are vital sources of food and biological products. However, viruses such as porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV) pose significant threats to the global swine industry, resulting in substantial financial losses. Currently, there are no available drugs or effective vaccines to combat these viruses. This study presents a small molecule, denoted as C14, which demonstrates promising potential to target porcine CD163, RNA-dependent RNA polymerase (RdRp) of PRRSV, and S273R of ASFV, and exhibits activity against both PRRSV (half maximal effective concentration [EC] = 0.34 μM) and ASFV (EC < 0.1 μM). By employing the strategy of similar topological structure binding properties of protein targets (STSBPT), interactions between C14 and targets were further analysed. The results indicate that the 5-Å regions of C14 within the active pockets of these macromolecular targets exhibit highly similar structural features, which may facilitate the development of antiviral drugs. Chemical synthesis, docking simulations, and antiviral activity assays were further conducted, and it was found that the structure of C14 is devoid of redundant elements, making it a prime candidate as core scaffold for subsequent structural optimization. This study provides a valuable reference for the development of multi-target antiviral drugs against PRRSV and ASFV.
猪是食物和生物制品的重要来源。然而，诸如猪繁殖与呼吸综合征病毒（PRRSV）和非洲猪瘟病毒（ASFV）等病毒对全球养猪业构成了重大威胁，导致了巨大的经济损失。目前，尚无对抗这些病毒的可用药物或有效疫苗。本研究提出了一种小分子，命名为C14，它显示出靶向猪CD163、PRRSV的RNA依赖性RNA聚合酶（RdRp）和ASFV的S273R的潜在前景，并对PRRSV（半数最大有效浓度[EC]=0.34μM）和ASFV（EC<0.1μM）均具有活性。通过采用蛋白质靶点相似拓扑结构结合特性（STSBPT）策略，进一步分析了C14与靶点之间的相互作用。结果表明，C14在这些大分子靶点活性口袋内的5埃区域表现出高度相似的结构特征，这可能有助于抗病毒药物的开发。进一步进行了化学合成、对接模拟和抗病毒活性测定，发现C14的结构没有冗余元素，使其成为后续结构优化的核心支架的主要候选物。本研究为开发针对PRRSV和ASFV的多靶点抗病毒药物提供了有价值的参考。
