Recent Advances in PROTAC Technology Toward New Therapeutic Modalities

Proteolysis targeting chimeras (PROTACs) have emerged as a powerful technology for the degradation of disease‐related proteins by the hijacking of the endogenous ubiquitin‐proteasome system. A multitude of bifunctional PROTACs have been developed using small‐molecule ligands; one ligand binds to the...

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Bibliographic Details
Published in:Chemistry & biodiversity 2022-11, Vol.19 (11), p.e202200828-n/a
Main Authors: Yokoo, Hidetomo, Naganuma, Miyako, Oba, Makoto, Demizu, Yosuke
Format: Article
Language:English
Subjects:
Allosteric properties
Binding
Chimeras
Drug resistance
Ligands
new modality
Nucleic acids
nucleotide
Nucleotides
Oligopeptides
peptide
Peptides
PROTAC
Proteasomes
Proteins
Proteolysis
Selectivity
small molecule
Technology
Ubiquitin
Ubiquitin-protein ligase
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Summary:Proteolysis targeting chimeras (PROTACs) have emerged as a powerful technology for the degradation of disease‐related proteins by the hijacking of the endogenous ubiquitin‐proteasome system. A multitude of bifunctional PROTACs have been developed using small‐molecule ligands; one ligand binds to the target protein of interest and one ligand binds to an E3 ligase. The characteristics of those PROTACs vary, including their reversible or irreversible covalent binding to the target protein, their binding to orthosteric and allosteric sites, their agonist or antagonist activity, and their use of multiple ligands. In addition, oligopeptides and nucleotides have recently been used as alternative targeting ligands. The properties of PROTACs, such as selectivity, delivery and sensitivity to drug resistance, can be improved through the use of a variety of targeting ligand modalities. This minireview introduces the mechanisms and behavior of small‐molecule based PROTACs as well as targeted proteolysis techniques using peptides and nucleic acids as targeting ligands.
ISSN:1612-1872
1612-1880
DOI:10.1002/cbdv.202200828