Sun Yuan, Shu Xiaoyang, Chen Lu, Shang Weijuan, Zhang Yumin, Xiao Gengfu, Zhang Leike
State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
PLoS Pathog. 2025 Sep 8;21(9):e1013492. doi: 10.1371/journal.ppat.1013492. eCollection 2025 Sep.
Coronavirus, a large family of positive-sense RNA viruses, are responsible for both mild and severe respiratory illnesses, ranging from the common cold to life-threatening conditions. Despite significant advances in vaccine and antiviral development, the high mutability of human coronaviruses (HCoVs), such as SARS-CoV-2, presents a major challenge in treating these infections. Effective, broad-spectrum antiviral drugs are urgently needed to address both current and future HCoV outbreaks. Here, we conducted high-throughput screening of a natural product library containing 3407 compounds to identify potential antiviral agents against HCoV-OC43 and HCoV-229E. We identified several natural products with inhibitory effects on HCoV-229E, HCoV-OC43, and the SARS-CoV-2 variants Delta (B.1.617.2) and Omicron (BA.5) in vitro without evident cytotoxicity. Among these, dibenzoylmethane (DBM) not only demonstrated broad-spectrum anticoronavirus activity in vitro but also effectively inhibited HCoV-OC43 replication in a BALB/c mouse model. Pharmacokinetic analysis revealed that DBM, when administered orally, maintained effective concentrations in the blood over an extended period, suggesting its suitability for oral administration. Mechanistically, DBM was found to regulate caspase-6, a host factor that suppresses interferon signalling and promotes HCoV replication. These findings highlight DBM as a promising candidate for the development of therapeutics targeting HCoVs, offering potential for treating infections by both established and emerging HCoVs.
冠状病毒是一类正链RNA病毒大家族，可导致从普通感冒到危及生命的各种轻重程度的呼吸道疾病。尽管在疫苗和抗病毒药物研发方面取得了重大进展，但人类冠状病毒（HCoV），如严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的高变异性，给治疗这些感染带来了重大挑战。迫切需要有效、广谱的抗病毒药物来应对当前和未来的HCoV疫情。在此，我们对一个包含3407种化合物的天然产物文库进行了高通量筛选，以鉴定针对HCoV-OC43和HCoV-229E的潜在抗病毒剂。我们鉴定出了几种对HCoV-229E、HCoV-OC43以及SARS-CoV-2变异株德尔塔（B.1.617.2）和奥密克戎（BA.5）具有体外抑制作用且无明显细胞毒性的天然产物。其中，二苯甲酰甲烷（DBM）不仅在体外表现出广谱抗冠状病毒活性，还在BALB/c小鼠模型中有效抑制了HCoV-OC43的复制。药代动力学分析表明，DBM口服给药后能在较长时间内维持血液中的有效浓度，表明其适合口服给药。从机制上讲，发现DBM可调节半胱天冬酶-6，这是一种抑制干扰素信号传导并促进HCoV复制的宿主因子。这些发现突出了DBM作为开发针对HCoV的治疗药物的有前景的候选物，为治疗既有和新出现的HCoV感染提供了潜力。
