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

Recent studies have reported that several emerging SL-CoVs, including WIV1, SHC014, and Rs3367, have the potential to infect humans with high virulence by further evolution or direct gene recombination with SARS-CoV (9, 11) . We found that the HR sequences of these SL-CoVs are the same as those of SARS-CoV, and we predicted that EK1 could prevent infection by these SL-CoVs. As (A) Side chain-to-side chain hydrophilic interactions between EK1 and HR1. Side chains of EK1 and HR1 residues involved in these interactions are shown as cyan and gray stick models, respectively, and are similarly color-coded. At least four pairs of this hydrophilic interaction are conserved across different EK1-HR1 complexes: Y30 EK1 forms similar polar interactions with Q1009 MERS (left), Q917 SARS (middle), or T817 229E (right); E27 EK1 forms similar polar interactions with Q1009 MERS (left), Q917 SARS (middle), or S820 229E (right); E15 EK1 forms salt bridges with K1021 MERS (left), K929 SARS (middle), or K832 229E (right); and T8 EK1 makes similar interactions with N1028 MERS (left), Q936 SARS (middle), or Q839 229E (right). The conserved HR1 residues mentioned above are highlighted with cyan boxes. (B) Main chain-to-side chain hydrophilic interactions between EK1 and HR1. EK1 and HR1 residues involved in these interactions are shown as green and gray stick models, respectively. The main-chain atoms of HR1 residues are not shown for clarity. Similar to the side chain-to-side chain interactions, main chain-to-side chain interactions are also highly conserved across different EK1-HR1 complexes. The HR1 residues involved in conserved interactions are highlighted with red boxes. expected, EK1 efficiently inhibited SL-CoV S protein-mediated cellcell fusion. Consistent with previous studies (9, 11) , we herein also failed to establish a SHC014 pseudovirus using an HIV-1 backbone vector; therefore, we assessed the antiviral effect of EK1 only on WIV1 and Rs3367 pseudovirus infection and found that EK1 exhibited effective inhibitory activity against these two SL-CoVs. In addition, some animal CoVs within the CoV family are very close to HCoV, such as bovine coronavirus (BCoV) and MHV. The HR sequences of these CoVs are very similar to those of OC43, indicating that peptide EK1 will likely also be effective on these viruses.