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Related Concept Videos

Ribozymes02:47

Ribozymes

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Ribozymes02:47

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The term ribozyme is used for RNA that can act as an enzyme. Ribozymes are mainly found in selected viruses, bacteria, plant organelles, and lower eukaryotes. Ribozymes were first discovered in 1982 when Tom Cech’s laboratory observed Group I introns acting as enzymes. This was shortly followed by the discovery of another ribozyme, Ribonulcease P, by Sid Altman’s laboratory. Both Cech and Altman received the Nobel Prize in chemistry in 1989 for their work on ribozymes.
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The Proteasome01:13

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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The presence of electron-donating, electron-withdrawing, or conjugating groups adjacent to a radical center, imparts electronic stabilization to the radicals. Examples of such electronically-stabilized radicals are triphenylmethyl, tetramethylpiperidine‐N‐oxide, and 2,2‐diphenyl‐1‐picrylhydrazyl. These radicals are remarkably stable and are known as persistent radicals. Some of the persistent radicals can even be isolated and purified.
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Related Experiment Video

Updated: Jan 6, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Tricarbonyl Rhenium-Based PROTACs Degrade the SARS-CoV-2 Mpro Protease.

Liuruiqi Luo1, Yuxiang Lu1, He Meng1

  • 1MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, IGCME, School of Chemistry, Sun Yat-Sen University, Guangzhou, China.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|November 30, 2025
PubMed
Summary

Researchers developed metallo-PROTACs, a novel approach using metal complexes for targeted protein degradation. This strategy enhances cellular uptake and potency, overcoming key limitations of traditional PROTACs.

Keywords:
PROTACSARS‐CoV‐2 main proteasemetal complexesprotein degradation

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) via proteolysis-targeting chimeras (PROTACs) presents an alternative to traditional inhibitors.
  • Key challenges in PROTAC development include ligand discovery and achieving sufficient cellular permeability.

Purpose of the Study:

  • To develop a novel metallo-PROTAC (Re2) to overcome PROTAC limitations.
  • To evaluate Re2's efficacy in degrading SARS-CoV-2 main protease (Mpro) and assess its cellular uptake.

Main Methods:

  • Design and synthesis of Re2, a metallo-PROTAC combining a rhenium(I) complex warhead with a cereblon E3 ligase ligand.
  • In vitro and ex vivo assays to assess Mpro degradation, covalent binding, and ubiquitin-proteasome system dependence.
  • Cellular uptake and accumulation studies comparing Re2 with its demetallated counterpart.

Main Results:

  • Re2 achieved effective intracellular Mpro degradation at 100 nM within 72 hours.
  • Confirmed covalent Mpro binding and ubiquitin-proteasome system-dependent degradation.
  • Metalation significantly enhanced cellular uptake and accumulation (3-4 fold) compared to the organic analog.

Conclusions:

  • Metallo-PROTACs represent a potent strategy for enhancing PROTAC efficacy and cellular delivery.
  • Metal complexes can overcome intrinsic PROTAC permeability barriers.
  • This approach offers a promising avenue for designing highly potent PROTACs.