Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The discovery of drugs that cause the degradation of their target proteins has been largely serendipitous. Here we report that the
tert-butyl carbamate
-protected arginine (Boc(3)Arg) moiety provides a general strategy for the design of degradation-inducing inhibitors. The covalent inactivators ethacrynic acid and thiobenzofurazan cause the specific degradation of glutathione-S-transferase when linked to Boc(3)Arg. Similarly, the degradation of dihydrofolate reductase is induced when cells are treated with the noncovalent inhibitor trimethoprim linked to Boc(3)Arg. Degradation is rapid and robust, with 30%-80% of these abundant target proteins consumed within 1.3-5 hr. The
proteasome
is required for Boc(3)Arg-mediated degradation, but ATP is not necessary and the ubiquitin pathways do not appear to be involved. These results suggest that the Boc(3)Arg moiety may provide a general strategy to construct inhibitors that induce targeted protein degradation.
...
PMID:Inhibitor mediated protein degradation. 2263 14
Targeted protein degradation is a promising strategy for drug design and functional assessment. Several small molecule approaches have been developed that localize target proteins to ubiquitin ligases, inducing ubiquitination and subsequent degradation by the 26S
proteasome
. We discovered that the degradation of a target protein can also be induced by a recognition ligand linked to
tert-butyl carbamate
(Boc
3
)-protected arginine (B
3
A). Here, we show that this process requires the
proteasome
but does not involve ubiquitination of the target protein. B
3
A does not perturb the structure of the target protein; instead, a B
3
A-ligand stabilizes its target protein. B
3
A ligands stimulate activity of purified 20S
proteasome
, demonstrating that the tag binds directly to the 20S
proteasome
. Moreover, purified 20S
proteasome
is sufficient to degrade target proteins in the presence of their respective B
3
A-linked recognition ligands. These observations suggest a simple model for B
3
A-mediated degradation wherein the B
3
A tag localizes target proteins directly to the 20S
proteasome
. Thus, B
3
A ligands are the first example of a ubiquitin-free strategy for targeted protein degradation.
...
PMID:Boc
3
Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome. 2770 67
