The ongoing emergence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019
(COVID-19) vaccines and therapeutic medications, making the development of effective
therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of
SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). However, the structural instability of
polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing
clinical trials, asse... More
The ongoing emergence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019
(COVID-19) vaccines and therapeutic medications, making the development of effective
therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of
SARS-CoV-2 3-chymotrypsin-like protease (3CLpro). However, the structural instability of
polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing
clinical trials, assessing their potential to inhibit SARS-CoV-2 3CLpro. Exifone and benserazide hydrochloride were identified as the inhibitors of SARS-CoV-2 3CLpro among these
compounds, using a fluorescence resonance energy transfer (FRET)-based assay. Benserazide hydrochloride was confirmed as a covalent binder to SARS-CoV-2 3CLpro through
time-dependent inhibition and kinetic analysis, with its binding mode elucidated by molecular docking. Notably, exifone not only inhibited the protease activity but also blocked
the interaction between the host cell receptor angiotensin-converting enzyme 2 (ACE2)
and the SARS-CoV-2 spike protein receptor binding domain (S-RBD), as identified by surface plasmon resonance (SPR) and flow cytometry. Additionally, exifone demonstrated
antiviral activity against various SARS-CoV-2-S pseudovirus variants. In conclusion, the
discovery of exifone and benserazide hydrochloride underscores the potential of polyphenols in developing conserved 3CLpro inhibitors for coronaviruses, offering new strategies for the rapid development of effective drugs against both current and future coronavirus pandemics.
