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The Proteasome Structure01:17

The Proteasome Structure

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
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Related Experiment Video

Updated: Jan 8, 2026

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors.

Haixia Su1,2, Tianqing Nie1,3,4, Guofeng Chen5,1

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 13, 2025
PubMed
Summary

Developing broad-spectrum antivirals is crucial for combating coronavirus outbreaks. A new compound, compound 8, shows potent inhibition against 32 3C-like proteases, offering a promising pan-coronavirus therapeutic strategy.

Keywords:
3C‐like proteaseconservation analysis of the binding pocketco‐crystal structurestructure‐based drug designultra‐broad‐spectrum inhibitors

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Area of Science:

  • Virology
  • Drug Discovery
  • Structural Biology

Background:

  • Recurrent coronavirus outbreaks and zoonotic origins highlight the need for broad-spectrum antiviral therapies.
  • The conserved 3C-like protease (3CLpro) is a validated drug target for pan-coronavirus therapeutics due to its essential role in viral replication and druggability.

Purpose of the Study:

  • To evaluate approved 3CLpro inhibitors against a panel of coronaviruses.
  • To develop novel, ultra-broad-spectrum 3CLpro inhibitors through structure-based optimization.
  • To provide a design strategy for potential pan-coronavirus therapeutics.

Main Methods:

  • Enzymatic assays were used to determine the inhibitory activity of nirmatrelvir, ensitrelvir, and simnotrelvir against fifteen 3CLpro enzymes.
  • Structure-based drug design and optimization of nirmatrelvir led to the identification of compound 8.
  • Compound 8's efficacy was tested against 32 3CLpro enzymes, including those from newly identified human coronaviruses and nirmatrelvir-resistant mutants, along with in vitro antiviral assays.

Main Results:

  • Approved 3CLpro inhibitors demonstrated potent activity against Beta-CoVs but reduced potency against other genera, particularly α-CCoV-HuPn-2018 and δ-PDCoV.
  • Compound 8 exhibited potent inhibition against a panel of 32 3CLpro enzymes (IC50s: 19–146 nm), including significant activity against α-CCoV-HuPn-2018 (61 nm) and δ-PDCoV (81 nm).
  • Compound 8 effectively inhibited nirmatrelvir-resistant mutants and showed broad-spectrum antiviral efficacy in cell-based assays.

Conclusions:

  • A small, non-cyclic P2 segment and a P4 segment of suitable size are key features for designing ultra-broad-spectrum 3CLpro inhibitors.
  • Compound 8 represents a promising lead candidate for developing pan-coronavirus therapeutics.
  • The study provides a proof-of-concept and guide for future development of broad-spectrum antiviral agents against diverse coronaviruses.