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Modelled peptides inhibit SARS-CoV-2 main protease

Simulations prefer a neutral His41/Cys145 dyad and guided four designed peptides that bind the Mpro dimer and inhibit substrate cleavage with IC50 values of 3–5 μM.

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What protonation state of the His-41/Cys-145 dyad is computed to be preferred with unreacted substrate?

The neutral dyad; a thiolate would be more reactive toward electrophiles.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

How much higher in energy is the ion pair versus the neutral dyad?

28.5 kJ mol−1 after ωB97X-D correction of the QM/MM profile.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

Which four peptides were synthesised to test the designs?

p12, p13, p15 and p16 as C-terminal carboxamides by solid-phase synthesis.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

What IC50 range did those peptides show?

3.11–5.36 μM, similar potency across all four.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

How was inhibition mode probed versus substrate concentration?

IC50 versus 2–40 μM s01 (Km ~ 14.4 μM).

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

What did non-denaturing MS show for p12/p13?

Complexes of the Mpro dimer with the peptides, plus reduced substrate-product complexes.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

How much did 8-fold peptide excess slow s01 depletion?

To 95/91/70/78% versus >98% without inhibitor.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

Which H-bonds hold substrates in MD?

Four backbone H-bonds: Glu-166 at S3 and Thr-26 at S2′.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

How similar are peptide and cluster-5 fragment poses?

Both H-bond His-163 and Glu-166 and occupy S1/S2 similarly.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

How many substrate 11-mers were modelled?

Eleven cleavage-site peptides from P6 to P5′.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified

What other residues participate in dyad proton transfer besides His-41/Cys-145?

His-163, His-164, Asp-187 and a structured water.

Source: Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding · DOI · quote verified