Abstract
Pathogenic coronaviruses are a major threat to global public health, as exemplified by severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV, and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound 1 day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses.
Highlights
Coronaviruses are a large group of viruses that can cause a wide variety of diseases in humans and animals [1]
Global outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from animal reservoirs, including Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19)
The activity of compounds 6a-k and 7ak against the 3C-like protease (3CLpro) enzymes of MERS-CoV, SARS-CoV and SARS-CoV-2 was evaluated in a fluorescence resonance energy transfer (FRET) enzyme assay (Table 1, Table S1)
Summary
Coronaviruses are a large group of viruses that can cause a wide variety of diseases in humans and animals [1]. Human coronaviruses generally cause the common cold, a mild upper respiratory illness. Global outbreaks of new human coronavirus infections with severe respiratory disease have periodically emerged from animal reservoirs, including Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV) and, most recently, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). Genetic analysis of SARS-CoV-2 revealed that it is closely related to SARS-like beta-coronaviruses of bat origin, bat-SL-CoVZC45 and bat-SL-CoVZXC21 [2]. Despite the periodic emergence of new coronaviruses capable of infecting humans, there are currently no licensed vaccines or antiviral drugs against any coronaviruses, underscoring the urgent need for the development of preventive and therapeutic measures against pathogenic coronaviruses
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.
