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. 2020 Apr 22;eabb4489.
doi: 10.1126/science.abb4489. Online ahead of print.

Structure-based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

Free PMC article

Structure-based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

Wenhao Dai et al. Science. .
Free PMC article


SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (Mpro) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at 1.5 Å resolution, showed that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of Mpro Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity, suggesting that these compounds are promising drug candidates.


Fig. 1
Fig. 1. Design strategy of novel SARS-CoV-2 main protease inhibitors and the chemical structures of 11a and 11b.
Fig. 2
Fig. 2. Inhibitory activity profiles of compounds 11a (A) and 11b (B) against SARS-CoV-2 Mpro.
Fig. 3
Fig. 3. Mpro-inhibitor binding modes for 11a and 11b.
(A) Cartoon representation of the crystal structure of SARS-CoV-2 Mpro in complex with 11a. The compound 11a is shown as magenta sticks; water molecules shown as red spheres. (B) Close-up view of the 11a binding pocket. Four subsites, S1′, S1, S2 and S4, are labeled. The residues involved in inhibitor binding are shown as wheat sticks. 11a and water molecules are shown as magenta sticks and red spheres, respectively. Hydrogen bonds are indicated as dashed lines. (C) Schematic diagram of SARS-CoV-2 Mpro-11a interactions shown in (B). (D) Comparison of the binding modes between 11a and 11b for SARS-CoV-2 Mpro. The major differences between 11a and 11b are marked with dashed circles. The compounds of 11a and 11b are shown as magenta and yellow sticks, respectively. (E) Close-up view of the 11b binding pocket. Hydrogen bonds are indicated as dashed lines. (F) Schematic diagram of SARS-CoV-2 Mpro-11b interactions shown in (E).
Fig. 4
Fig. 4. Comparison of the inhibitor binding modes in SARS-CoV and SARS-CoV-2 Mpros.
(A) Comparison of binding modes of 11a in SARS-CoV-2 Mpro with those of N1, N3 and N9 in SARS-CoV Mpro. SARS-CoV-2 Mpro-11a (wheat, PDB code: 6LZE), SARS-CoV Mpro-N1 (sky blue, PDB code:1WOF), SARS-CoV Mpro-N3 (gray, PDB code: 2AMQ) and SARS-CoV Mpro-N9 (olive, PDB code: 2AMD).11a, N1, N3 and N9 are shown in magenta, cyan, dirty violet and salt, respectively. (B) Comparison of the 11a and N3 binding pockets. Residues in Mpro-11a structure and Mpro-N3 structure are colored in wheat and gray, respectively. 11a and N3 are shown as sticks colored in magenta and dirty violet, respectively. (C) Comparison of binding modes of 11b in SARS-CoV-2 Mpro with those of N1, N3 and N9 in SARS-CoV Mpro. SARS-CoV-2 Mpro-11b (pale cyan, PDB code: 6M0K). 11b, N1, N3 and N9 are shown in yellow, cyan, dirty violet and salt, respectively. (D) Comparison of the 11b and N9 binding pockets. Residues in Mpro-11b structure and Mpro-N9 structure are colored in pale cyan and olive, respectively. 11b and N9 are shown as sticks colored in yellow and salt, respectively.
Fig. 5
Fig. 5. In vitro inhibition of viral main protease inhibitors against SARS-CoV-2.
(A and B) Vero E6 cells were treated with a series concentration of indicated compounds 11a and 11b and infected with SARS-CoV-2 at an MOI of 0.05. At 24 hours post infection, viral yield in the cell supernatant was quantified by plaque assay. The cytotoxicity of these compounds in Vero E6 cells was also determined by using CCK8 assays. The left and right Y-axis of the graphs represent mean % inhibition of virus yield and mean % cytotoxicity of the drugs, respectively. (C and D) Viral RNA copy numbers in the cell supernatants were quantified by qRT-PCR. Data are mean ± SD, n = 3 biological replicates.

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