Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus

doi: 10.1080/14756366.2024.2390909

Figure Lengend Snippet: Inhibitory effect of compounds 1 – 10 against 3CL pro at 1.0 μM. Note: n = 3, mean ± SD. Compared with the DHM: * p < .05 and ** p < .01.

Article Snippet: The inhibitory activity of DHM derivatives against SARS-CoV-2 3CL pro was detected by using the SARS-CoV-2 3CL pro Inhibitor Screening Kit (Enhanced) #P0315M (Beyotime, China) .

Techniques:

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus

doi: 10.1080/14756366.2024.2390909

Figure Lengend Snippet: Molecular docking score and IC 50 of compounds 1 – 10 ^a with 3CL pro .

Article Snippet: The inhibitory activity of DHM derivatives against SARS-CoV-2 3CL pro was detected by using the SARS-CoV-2 3CL pro Inhibitor Screening Kit (Enhanced) #P0315M (Beyotime, China) .

Techniques: Binding Assay

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus

doi: 10.1080/14756366.2024.2390909

Figure Lengend Snippet: SAR of dihydromyricetin derivatives inhibition SARS-CoV-2 3CL pro .

Article Snippet: The inhibitory activity of DHM derivatives against SARS-CoV-2 3CL pro was detected by using the SARS-CoV-2 3CL pro Inhibitor Screening Kit (Enhanced) #P0315M (Beyotime, China) .

Techniques: Inhibition

Journal: Journal of Enzyme Inhibition and Medicinal Chemistry

Article Title: Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus

doi: 10.1080/14756366.2024.2390909

Figure Lengend Snippet: Molecular docking of compounds 1 ( DHM ), 3 , 5, and 10 with 3CL pro . (A) Schematic diagram, (B) 3D enlargement, and (C) 2D schematic of the hydrogen-bond interaction between compounds 1, 3, 5, 10, and 3CL pro , respectively.

Article Snippet: The inhibitory activity of DHM derivatives against SARS-CoV-2 3CL pro was detected by using the SARS-CoV-2 3CL pro Inhibitor Screening Kit (Enhanced) #P0315M (Beyotime, China) .

Techniques:

Journal: Nature Communications

Article Title: Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

doi: 10.1038/s41467-023-42102-y

Figure Lengend Snippet: a The chemical structure of boceprevir and its inhibitory activity against SARS-CoV-2 3CL pro (expressed as IC 50 ). P1’-P4 segments of boceprevir are colored in cyan, magenta, olive, orange, and green, respectively. b Molecular surface representation of boceprevir interacting with the S1ʹ-S4 subsites of SARS-CoV-2 3CL pro (PDB code: 6XQU). Boceprevir is shown in gray balls and sticks. The S1’-S4 subsites are colored cyan, magenta, yellow, orange, and green, respectively. c – e Chemical structures and in vitro biochemical and biophysical characterization of compounds that were designed to favorably interact with the S1’(C145) and S1 ( c ), S2 ( d ) and S4 ( e ) subsites of SARS-CoV-2 3CL pro . IC 50 is the half-maximal inhibitory concentration of the compound against the protease determined by the enzymatic inhibition assay. K d is the dissociation constant of the compound from the C145G mutant 3CL pro measured by ITC. GSH t 1/2 is the half-life of the electrophile warhead to react with glutathione. EC 50 CP and CC 50 are the half-maximal effective concentration in the presence of the P-glycoprotein efflux inhibitor CP-100356 and the half-maximal cytotoxic concentration of the compound in Vero E6 cells, respectively. Three independent experiments were performed to determine the IC 50 , GSH t 1/2 , K d , EC 50 CP , and CC 50 values.

Article Snippet: Very recently, the noncovalent, nonpeptidic, orally bioavailable small molecule SARS-CoV-2 3CL pro inhibitor ensitrelvir (S-217622) developed by Shionogi has also been granted EUA in Japan for COVID-19 therapeutic intervention.

Techniques: Activity Assay, In Vitro, Concentration Assay, Inhibition, Mutagenesis

Journal: Nature Communications

Article Title: Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

doi: 10.1038/s41467-023-42102-y

Figure Lengend Snippet: a Binding mode of compound 2 (light purple sticks, PDB code: 8IFQ) with SARS-CoV-2 3CL pro . The protease is shown in surface representation. The S1’-S4 subsites are colored as follows: S1’, cyan; S1, magenta; S2, yellow; S3, orange; and S4, green. b Thermodynamic measurements of compounds 2 and 7 , nirmatrelvir, and simnotrelvir binding to SARS-CoV-2 3CL pro . The thermodynamic profiles are shown as histograms with the Gibbs free energy of binding (Δ G ; light blue), enthalpy (Δ H ; salmon) and entropy (− T Δ S ; light orange). The data are plotted as the mean ± SD from three independent experiments. c – g Comparison of the binding modes of compound 7 (salmon sticks, PDB code: 8IFS), simnotrelvir (yellow sticks, PDB code: 8IGX) and nirmatrelvir (gray sticks, PDB code: 8IGY) with SARS-CoV-2 3CL pro by superimposition of their crystal structures. Residues 40-51 (S2 helix) and 187-192 (S4 loop) of SARS-CoV-2 3CL pro are shown as cartoons. The distances are denoted as dashed lines. h , i Interactions between the P2 segment of simnotrelvir ( h ) and nirmatrelvir ( i ) (balls and sticks) and the S2 subsite residues (cyan sticks). Source data are provided as a Source Data file.

Article Snippet: Very recently, the noncovalent, nonpeptidic, orally bioavailable small molecule SARS-CoV-2 3CL pro inhibitor ensitrelvir (S-217622) developed by Shionogi has also been granted EUA in Japan for COVID-19 therapeutic intervention.

Techniques: Binding Assay, Comparison

Journal: Nature Communications

Article Title: Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

doi: 10.1038/s41467-023-42102-y

Figure Lengend Snippet: a Rat plasma concentration of simnotrelvir following a single oral dose of 15 mg/kg with or without 30 mg/kg ritonavir (RTV, n = 6 for each group). b Monkey plasma concentration of simnotrelvir following a single oral dose of 5 mg/kg with or without 15 mg/kg ritonavir ( n = 6 for each group). c Heatmap of the measured IC 50 values of simnotrelvir against 6 human proteases, 413 human kinases and 47 human ADR targets (light blue); 5 safety assays (gray); 7 human CYP enzymes (light purple); 3CL pro s of 7 human coronaviruses (light orange); and 3CL pro s of 6 SARS-CoV-2 variants (light yellow). The different colors represent the measured IC 50 values or results (positive or negative). d , e Preclinical toxicokinetic exposure of rats ( d ) and monkeys ( e ) to simnotrelvir at Day 14. Rats were orally dosed with 30 mg/kg ( n = 8), 180 mg/kg ( n = 8) and 1000 mg/kg ( n = 8) simnotrelvir once daily for 14 days. Monkeys were orally dosed with 40 mg/kg (20 mg/kg, BID, n = 6), 160 mg/kg (80 mg/kg, BID, n = 6) and 600 mg/kg (300 mg/kg, BID, n = 10) simnotrelvir for 14 days. f Plasma exposure of uninfected male C57BL/J mice treated with simnotrelvir 200 mg/kg or 50 mg/kg plus 50 mg/kg ritonavir BID for one day ( n = 3 for each time point). BQL indicates that the data were below the quantification limit. g Tissue distribution of simnotrelvir in uninfected male C57BL/J mice after a single oral administration of 200 mg/kg simnotrelvir plus 50 mg/kg ritonavir ( n = 24 for each group). The unit of concentrations is ng/mL for plasma and ng/g for lung and brain tissues. The cellular EC 90 total and EC 50 total against SARS-CoV-2 Delta were calculated by dividing the cellular EC 90 CP and EC 50 CP by the plasma unbound fraction, respectively. The data are plotted as the mean ± SD. Source data are provided as a Source Data file.

Article Snippet: Very recently, the noncovalent, nonpeptidic, orally bioavailable small molecule SARS-CoV-2 3CL pro inhibitor ensitrelvir (S-217622) developed by Shionogi has also been granted EUA in Japan for COVID-19 therapeutic intervention.

Techniques: Clinical Proteomics, Concentration Assay

Journal: Research Square

Article Title: SARS-CoV-2 3CL-protease inhibitors derived from ML300: investigation of P1 and replacements of the 1,2,3-benzotriazole

doi: 10.21203/rs.3.rs-2880312/v1

Figure Lengend Snippet: Clinical agents and pre-clinical non-covalent SARS-CoV-2 3CL pro inhibitors: 1 (Nirmatrelvir), 2 (Ensitrelivr), 3 , 4 , and ML300 derived 5 (CCF0058981) .

Article Snippet: In 2021, Pfizer received emergency use authorization for the use of their covalent SARS-CoV-2 3CL pro inhibitor, PF-07321332 or nirmatrelvir ( , ) for the treatment of acute disease.

Techniques: Derivative Assay

Journal: Antiviral Research

Article Title: Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

doi: 10.1016/j.antiviral.2023.105586

Figure Lengend Snippet: Structure of covalent SARS-CoV-2 3CL pro inhibitor PF-07321332 and non-covalent 3CL pro inhibitor ML188 .

Article Snippet: Recently, Shionogi Inc. disclosed the discovery of a non-covalent 3CL pro inhibitor S-217622 , ( ) which obtained emergency regulatory approval in Japan recently on Nov 22, 2022 ( ).

Techniques:

Journal: Antiviral Research

Article Title: Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

doi: 10.1016/j.antiviral.2023.105586

Figure Lengend Snippet: X-ray crystal structure of YY-278 and 3CL pro . 3CL pro is shown as cartoon and colored in gray; residues involved in interaction with YY-278 are shown as ball-and-stick models and colored in green and YY-278 is colored in orange. Water molecules are displayed as red spheres. The additional water molecule identified in this structure is shown as purple sphere. Hydrogen bonds are indicated by yellow dashed lines.

Article Snippet: Recently, Shionogi Inc. disclosed the discovery of a non-covalent 3CL pro inhibitor S-217622 , ( ) which obtained emergency regulatory approval in Japan recently on Nov 22, 2022 ( ).

Techniques:

Journal: Antiviral Research

Article Title: Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2

doi: 10.1016/j.antiviral.2023.105586

Figure Lengend Snippet: SARS-CoV-2 3CL pro enzymatic inhibitory activities and antiviral activities against SARS-CoV-2 in A549-hACE2 cells.

Article Snippet: Recently, Shionogi Inc. disclosed the discovery of a non-covalent 3CL pro inhibitor S-217622 , ( ) which obtained emergency regulatory approval in Japan recently on Nov 22, 2022 ( ).

Techniques: