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

At the same time, sequence alignment between EK1 and HR2s from OC43, SARS-CoV, and MERS-CoV provided clues on the very limited inhibition breadth of SARS-HR2 and MERS-HR2. Although most residues that mediated hydrophobic (shaded orange and yellow) and side chain-to-side chain hydrophilic interactions (boxed in cyan) are conserved between EK1 and different HR2s, sequence variability does exist at positions V7, Y30, and some other ridge-packing residues ( fig. S7A ). We thus focused our analysis on these residues and their surrounding environments in different HCoVs' 3HR1 cores. In both solved structures of MERS(HR1)-EK1 and SARS(HR1)-EK1, V7 EK1 fits its side chain neatly into the hydrophobic pockets on these two 3HR1 cores ( fig. S7B, second and fourth panels) . Nevertheless, in the previously reported structure of the SARS-CoV fusion core, A1156 SARS , the equivalent of V7 EK1 in SARS-CoV, would occupy the same cavity loosely ( fig. S7B, third panel) , while T1257 MERS , the equivalent of V7 EK1 in MERS-CoV, could not fully bury its side chain owing to the polar nature of the Thr residue ( fig. S7B, first panel) . Thus, Val, in EK1 and OC43-HR2, is more effective in fitting the hydrophobic cavities at this position than Ala (seen in SARS-HR2) or Thr (seen in MERS-HR2) ( fig. S7B ).