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

No effective and broad-spectrum anti-HCoVs drugs or vaccines are currently available in the clinic. Notwithstanding, the RBD of the S protein has been proposed as a promising target for the develop-ment of specific antibodies and vaccines (39, 40) . For example, the RBD-specific antibody CDC2-C2 exhibits inhibitory activity against MERS-CoV infection. Nevertheless, administration of the single-antibody CDC2-C2 could result in the emergence of escape mutations in MERS-CoV RBD (41) . Unfortunately, the CoV S RBD is hypervariable throughout evolution, which has led to marked difference in host receptor usage in different HCoVs. Even when the same host receptor is used by different HCoVs, they frequently target different binding sites on the host receptor (42) . Therefore, specific RBD-targeting antibodies or vaccines inevitably lack broad-spectrum activity against HCoV infection. For example, Menachery et al. (9) found that a SARS-CoV RBD-specific antibody could not protect mice from infection by the chimeric virus with the SHC014 S proteins, although SHC014 has high homology with SARS-CoV and can bind the same host receptor ACE2. The lag time between emerging human CoV outbreaks and development of new prophylactic treatments or vaccines is of concern. Thus, there is an urgent need for the development of new, broad-spectrum drugs that target conserved sites in currently circulating and future emerging HCoVs so as to prepare for future outbreaks of yet unknown HCoVs.