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[Display omitted] • A series of peptidomimetic SARS-CoV-2 3CLpro inhibitors were synthesized and evaluated. • Potent compounds were discovered by changing the P 2 and P 4 position. • Compounds 1a and 2b showed excellent enzyme inhibitory potency and significant antiviral activity. • The metabolic stability of 1a and 2b in liver microsomes was significantly improved. In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P 2 and P 4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC 50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC 50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of peptidomimetic SARS-CoV-2 3CLpro inhibitors were synthesized and evaluated. • Potent compounds were discovered by changing the P 2 and P 4 position. • Compounds 1a and 2b showed excellent enzyme inhibitory potency and significant antiviral activity. • The metabolic stability of 1a and 2b in liver microsomes was significantly improved. In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P 2 and P 4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC 50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC 50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice. [ABSTRACT FROM AUTHOR]

• A native mass spectrometry-based affinity-selection coupled with a natural compound identification procedure was developed. • With the optimized method, compounds that bind to SARS-CoV-2 3CLpro were screened out from complex mixtures. • Protein-ligand complexes and stoichiometric numbers could be visualized and alerts could be given for nonspecific binding. • The binding affinity between protein and compound could be easily determined by mass spectrometry. [Display omitted] A native MS-based affinity-selection method was developed to screen compounds that target SARS-CoV-2 3CLpro from TCMs crude extracts. The 3C-like protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential to the virus life cycle and is supposed to be a potential target for the treatment of coronaviral infection. Traditional Chinese medicines (TCMs) have played an impressive role in the treatment of COVID-19 in China. The effectiveness of TCM formulations prompts scientists to take continuous effort on searching for bioactive small molecules from the ancient resources. Herein, we developed a native mass spectrometry-based affinity-selection method for rapid screening of active small molecules from crude herbal extracts applied for COVID-19 therapy. Six common herbs named Lonicera japonica, Scutellaria baicalensis, Forsythia suspensa, Glycyrrhiza uralensis, Cirsium japonicum, and Andrographis paniculata were investigated. After preliminary separation of the crude extracts, the fractions were incubated with 3CLpro. A native MS-based affinity screening assay was then conducted to search for the protein-ligand complexes. A UHPLC-Q/TOF-MS with UNIFI data acquisition and data processing software was applied to identify the hit compounds. Standard compounds were used to verify the outcomes. Among the 16 hits, three flavonoids, baicalein, scutellarein and ganhuangenin, were identified as potential noncovalent inhibitors against 3CLpro with IC 50 values of 0.94, 3.02, and 0.84 μM, respectively. Their binding affinities were further characterized by native MS, with K d values being 1.43, 3.85, and 1.09 μM, respectively. Overall, we established an efficient native MS-based strategy for discovering 3CLpro ligands from crude mixtures, which supplies a potential strategy of small molecule lead discovery from TCMs. [ABSTRACT FROM AUTHOR]

Previous researches suggested that polysaccharides from brown algae had anti-virus activity. We hypothesized that nature polysaccharide from marine plants might have the effect on anti-SARS-CoV-2 activity. By high throughput screening to target 3CLpro enzyme using polysaccharides library, we discover a crude polysaccharide 375 from seaweed Ecklonia kurome blocked 3CLpro enzymatic activity and shows good anti-SARS-CoV-2 infection activity in cell. Further, we show that homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro well and disturb spike protein binding to ACE2 receptor. The structure characterization uncovers that 37502 is alginate. These results imply that the bioactivities of 375 on SARS-CoV-2 may target multiple key molecules implicated in the virus infection and replication. The above results suggest that 375 may be a potential drug candidate against SARS-CoV-2. [Display omitted] [ABSTRACT FROM AUTHOR]