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 the early 1990s, a series of peptides derived from the HIV-1 gp41 HR2 (or CHR) domain, such as SJ-2176 (19) , DP-178 (later T20) (20) , and C34 (21) , were reported to have highly potent inhibitory activity against HIV-1 gp41-mediated membrane fusion and HIV-1 infection with IC 50 values at low nanomolar levels. Subsequently, numerous virus fusion inhibitory peptides overlapping the HR2 sequences of class I membrane fusion proteins from other enveloped viruses, including RSV (22) , Ebola virus (23), paramyxoviruses SV5 (24), and Nipah virus (25) , were also reported. In 2003, Bosch et al. (26) discovered that a soluble HR2 peptide derived from the MHV S protein HR2 region inhibited virus cell entry, suggesting that the S glycoprotein of CoV is a class I fusogen with the ability to form 6-HB during the S protein-mediated membrane fusion process. In 2004, the Bosch (43) and Jiang (18) groups independently reported that peptides derived from the HR2 region of SARS-CoV S protein could interact with the peptides from its HR1 region to form 6-HB and inhibited SARS-CoV S protein-mediated membrane fusion and SARS-CoV infection with moderate potency. In 2014, Lu et al. (27) reported that peptide derived from the MERS-CoV S-HR2 could competitively inhibit 6-HB formation, thereby preventing fusion of the virus with host cells.