A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike

Xia, Shuai; Yan, Lei; Xu, Wei; Agrawal, Anurodh Shankar; Algaissi, Abdullah; Tseng, Chien-Te K.; Wang, Qian; Du, Lanying; Tan, Wenjie; Wilson, Ian A.; Jiang, Shibo; Yang, Bei; Lu, Lu

Next, we assessed the protective effect of EK1 in vivo on OC43 and MERS-CoV infection mouse models. In the OC43-infected mouse model, we treated newborn mice with EK1 at a dose of 5 mg/kg or with PBS 30 min before or after challenge with HCoV-OC43 at 10 2 TCID 50 (50% tissue culture infectious dose). Body weight of mice in the viral control group decreased, starting from 5 days postinfection (dpi), and mice succumbed to infection by 10 dpi with 100% mortality (Fig. 3 , E to G). In contrast, the final survival rate of mice in the EK1 prophylactic and therapeutic groups was 100 and 66.7%, respectively (Fig. 3E) , and their body weight either appeared normal (prophylactic) or rapidly recovered at 16 dpi (therapeutic) (Fig. 3F ). Meanwhile, we tested the viral titers in brains of mice of all groups at 5 dpi. Infectious virus was readily detectable in the viral control group, whereas infectious virus titers were below the limit of detection (2 log TCID 50 /g) in the EK1 prophylactic mice or very low in the EK1 therapeutic mice (Fig. 3G) . However, the infectious virus titers in the brains of mice that died during EK1 therapeutic treatment were as high as those in the brains of viral control mice without EK1 treatment, while the viral titers in the brains of survival mice with EK1 therapeutic treatment and in those of normal control mice were both undetectable ( fig. S2E ). Consistently, the brains of mice that died during EK1 therapeutic treatment exhibited similar histopathological changes as those of the viral control mice, i.e., similar amount of vacuolation, degeneration, and infiltration ( fig. S2F ). In contrast, the brains of the survival mice with EK1 therapeutic treatment and those of the normal control mice showed no apparent histopathological changes ( fig. S2F ).