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

In total, we observed four ridge-packing interactions between the EK1 and 3HR1 cores. The ridge to which S29Y30 EK1 binds is surrounded by polar and positively charged residues in MERS-CoV and SARS-CoV but surrounded by polar and negatively charged residues in 229E [ fig. S7C (top panel) , side chains of surrounding residues are shown as stick models]. At this position, the polar pair "Ser-Tyr" in EK1 and OC43-HR2 appears to be more suitable than the "Ser-Leu" pair from SARS-HR2 in accommodating the opposite electrostatic environments in different HCoVs. Moreover, the aromatic ring of Tyr could also form additional polar interactions with HR1 side chains in different HCoVs (Fig. 6A) . Likewise, the ridges to which E15M16 EK1 binds also exhibited better shape complementarity to Met (in EK1 and OC43-HR2) than to Ile (in SARS-HR2). Collectively, it seems that EK1 and OC43-HR2 have more optimal amino acid choices at all the abovementioned critical positions, which likely accounts for their unique pan-CoV inhibitory activity.