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

Both hydrophobic pockets and ridges exist on the surface of 3HR1 cores (Fig. 5A) . Correspondingly, we observed two kinds of hydrophobic interactions between the EK1 and 3HR1 cores. In particular, certain EK1 residues insert their hydrophobic side chains into pockets on the 3HR1 cores (Fig. 5A , shown as orange stick models and hereafter named as "burying residues"), and other EK1 residues pack their side chains against hydrophobic ridges on the 3HR1 cores (Fig. 5A , shown as yellow stick models and hereafter named as "ridge-packing residues"). Note that the residues on HR1 that medi- . S5 ). Together, extensive and highly conserved hydrophobic and hydrophilic interactions between EK1 and 3HR1 cores endow EK1 with the ability to bind the 3HR1 cores from different HCoVs and, hence, the capability of blocking the association of different HR2s onto their corresponding 3HR1 cores (Fig. 2 ).