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
Structured fields used in claim comparison tables when every cited study has a complete layer.
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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