A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 11 2023
04 11 2023
Historique:
received:
05
01
2023
accepted:
13
10
2023
medline:
6
11
2023
pubmed:
5
11
2023
entrez:
5
11
2023
Statut:
epublish
Résumé
Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach.
Identifiants
pubmed: 37925433
doi: 10.1038/s41467-023-42546-2
pii: 10.1038/s41467-023-42546-2
pmc: PMC10625600
doi:
Substances chimiques
ELAV-Like Protein 1
0
RNA
63231-63-0
RNA-Binding Proteins
0
Proteolysis Targeting Chimera
0
ELAVL1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7093Informations de copyright
© 2023. The Author(s).
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