Abstract
The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19)
SARS-CoV-2 RNA has been frequently detected in fecal samples from COVID-19 patients with gastrointestinal symptoms, including abdominal pain, diarrhea, vomiting, anorexia and nausea, suggesting that SARS-CoV-2 may be transmitted through the fecal–oral pathway,[4,5] which further increases the difficulty in combating SARS-CoV-2 pandemic
EK1 and EK1C4 against wild-type SARS-CoV-2 PsV infection on Caco[2] cells. b, c Inhibitory activity of EK1 and EK1C4 against infection mediated by S protein of SARS-CoV-2 B.1.1.7 (b) and B.1.1.248 (c) variants on Caco[2] cells. d–g Anti-SARS-CoV-2 efficacy of EK1 and EK1C4 on PsV infection mediated by the S protein with single mutations, including K417N (d), E484K (e), N501Y (f), or D614G (g), respectively on Caco[2] cells. h-k Antiviral efficacy of EK1 and EK1C4 against PsV infection mediated by the S protein with combinational mutations, including K417N/ E484K (h), N501Y/ K417N (i) N501Y/E484K (j), and N501Y/ K417N/E484K (k), respectively, on Caco[2] cells
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). 2 transmits mainly through the respiratory pathway and may cause severe respiratory symptoms, such as dyspnea and even pulmonary failure.[3] SARS-CoV-2 RNA has been frequently detected in fecal samples from COVID-19 patients with gastrointestinal symptoms, including abdominal pain, diarrhea, vomiting, anorexia and nausea, suggesting that SARS-CoV-2 may be transmitted through the fecal–oral pathway,[4,5] which further increases the difficulty in combating SARS-CoV-2 pandemic. As the global pandemic of SARS-CoV-2 presents different states of infectivity in different countries, many variants have emerged and spread worldwide. The Alpha variant B.1.1.7 emerged in southeastern England in November
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
