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

The 3HR1 cores are shown as electrostatic surfaces. At the positions where the hydrophobic surface on the 3HR1 core is deeply concave (pockets), EK1 residues that bury over 70% of their side-chain solvent accessible surface (SAS) into these pockets are shown as orange stick models. At the locations where the hydrophobic surface on the 3HR1 core is relatively flat (ridges), EK1 residues that pack 50 to 70% of their side-chain SAS against these ridges are shown as light yellow stick models. EK1 residues are labeled, where those labeled in red form both hydrophobic and hydrophilic interactions with 3HR1 cores. (B) HR1 residues involved in interactions with EK1 are conserved across different HCoVs. EK1 and HR1 residues linked with dashed lines locate to the same layers on the 3HR1 triple helix. Burying EK1 residues are shaded orange, and ridge-packing EK1 residues are shaded light yellow. HR1 residues that mediate assembly of the 3HR1 cores are shaded orange, while those involved in ridge packing are shaded yellow. HR1 residues that mediate conserved side chain-to-side chain and side chain-to-main chain hydrophilic interactions with EK1 residues are highlighted with cyan and red boxes, respectively.