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.
Source
Discovery of SARS-CoV-2 M<sup>pro</sup> peptide inhibitors from modelling substrate and ligand binding
Study at a glance
- Design
- Other — Computational design plus biochemical IC50 assays of Mpro peptide inhibitors
- N
- Four designed peptides assayed in vitro — no sample cohort N
- Population
- SARS-CoV-2 main protease with designed peptide inhibitors
- Outcome
- Peptide IC50 values and substrate-depletion inhibition of Mpro
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Inspect source passages
Modelled peptides inhibit SARS-CoV-2 main protease
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
The ion-pair dyad is 28.5 kJ mol−1 higher than the neutral state.
Applying the free energy difference between ωB97X-D/6-31G(d) and DFTB3 at each reaction coordinate value as a correction to the combined QM/MM free energy profile in the case of HIE-163, the neutral catalytic dyad is preferred, with the ion pair being 28.5 kJ mol −1 higher in energy than the neutral state ().
Designed peptides had IC50 values from 3.11 μM to 5.36 μM.
All four designed peptides manifested similar potency with IC 50 values ranging from 3.11 μM to 5.36 μM ( and Fig.
What they did
Authors combined docking, MD, QM/MM and fragment clustering on SARS-CoV-2 Mpro, synthesised peptides p12, p13, p15 and p16, and measured inhibition and non-denaturing MS complexes versus 11-mer substrates.
What they found
The ion-pair dyad lies 28.5 kJ mol−1 above the neutral state. Designed peptides have IC50 3.11–5.36 μM; at 8-fold excess they cut s01 depletion from >98% to 70–95%. Binding modes mimic cluster-5 fragments and H-bond His-163/Glu-166.
The limits
What it doesn't show
These are micromolar peptides, not optimized oral antivirals, and the preferred dyad protonation is a computed free-energy result.
Key terms
- Mpro
- SARS-CoV-2 main protease (3CLpro) that cleaves viral polyproteins at 11 sites.
- Catalytic dyad
- His-41 and Cys-145 in the active site; modelled as neutral versus ion pair.
- P1 Gln
- Substrate residue before the scissile bond, a hallmark Mpro specificity.
- Non-denaturing MS
- Mass spectrometry of intact Mpro dimer–ligand complexes.
- Cluster 5 fragments
- XChem fragments sharing the His-163/Glu-166 H-bond motif used to design peptides.
Flashcards
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Quiz yourself
With unreacted substrate, the catalytic dyad is computed to be:
Common questions
Is the catalytic dyad predicted as charged?
No—neutral is preferred by 28.5 kJ mol−1 with unreacted substrate.
What IC50 range did designed peptides show?
3.11–5.36 μM.
How were peptides made?
Solid-phase synthesis with C-terminal carboxamide.
What does MS show?
Mpro dimer complexes with p12/p13 and reduced substrate turnover.
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