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

Similar to HR1 from -HCoVs, sequence alignment across HCoVs revealed that a 14-amino acid insertion also exists in the HR2 region of -HCoVs (Fig. 1C) . Such an insertion renders the HR2 helices of -HCoVs four turns longer than those of -HCoVs. The helical region of EK1 is only five turns long, much shorter than the nine-turn helix in 229E-HR2 (38) . Nevertheless, the burying residues in the extended region of EK1 and their equivalents in 229E-HR2 all neatly insert their side chains into corresponding . Furthermore, a total of 12 polar and electrostatic interactions occur between EK1 and 229E-HR1, including five side chain-to-side chain and seven side chain-to-main chain interactions [Fig. 6, A and B (right panel) ]. Together, these extensive hydrophobic and hydrophilic interactions preserve the high affinity of EK1 toward long HR1 HCoVs. That EK1 can form 6-HB structures with both short (SARS-CoV and MERS-CoV) and long (229E) HR1s highlights its broad structural compatibility in accommodating HR1s from different HCoVs, thus consolidating its broad-spectrum inhibitory effect against pan-CoVs.