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 potency of HR2-derived peptides in inhibiting corresponding virus-cell fusion varies significantly. For example, anti-HIV-1 peptide T20 is about 900-fold more potent than the anti-SARS-CoV peptide SC-1, yet only 30-fold more potent than the anti-MERS-CoV peptide HR2P (18, 27, 44) . It is known that HIV-1 and SARS-CoV each enter their target cells mainly through plasma and endosomal membrane fusion, respectively, while MERS-CoV could infect its target cells via both plasma and endosomal membrane fusion (18, 27, 44) . The vast differences seen in potency thus suggest that only a limited number of the EK1 peptides can get into the endosome to inhibit virus-cell fusion. Therefore, increasing the cell permeability of the fusion inhibitory peptides is expected to enhance the potency of these peptides. We have recently reported that addition of hydrocarbon stapling or a palmitic acid group (C16) to the MERS-CoV fusion inhibitory peptides significantly improves their antiviral potency and pharmacokinetic properties (45, 46) . In the near future, we will use the similar approaches to improving the antiviral activity of EK1.