Host E3 ligase HUWE1 attenuates the pro-apoptotic activity of the MERS-CoV accessory protein ORF3 by promoting its ubiquitin-dependent degradation

A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.

Download Full-text

From Inhibition to Degradation: Targeting the Anti-apoptotic Protein Myeloid Cell Leukemia 1(MCL1)

10.26434/chemrxiv.7722359 ◽

2019 ◽

Author(s):

James Papatzimas ◽

Evgueni Gorobets ◽

Ranjan Maity ◽

Mir Ishruna Muniyat ◽

Justin L. MacCallum ◽

...

Keyword(s):

Small Molecules ◽

E3 Ligase ◽

Myeloid Cell ◽

Cell Leukemia ◽

New Class ◽

Apoptotic Protein ◽

Family Protein ◽

Ubiquitination Pathway

<div> <div> <div> <p>Here we show the development of heterobifunctional small molecules capable of selectively targeting MCL1 using a Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitination pathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 family protein degraders. </p> </div> </div> </div>

Download Full-text

PHOTACs Enable Optical Control of Protein Degradation

10.26434/chemrxiv.8206688 ◽

2019 ◽

Cited By ~ 2

Author(s):

Martin Reynders ◽

Bryan Matsuura ◽

Marleen Bérouti ◽

Daniele Simoneschi ◽

Antonio Marzio ◽

...

Keyword(s):

Protein Degradation ◽

E3 Ligase ◽

Optical Control ◽

Cellular Proteins ◽

Bifunctional Molecules ◽

Protein Levels ◽

Lead Compounds ◽

Subsequent Degradation ◽

Temporal And Spatial ◽

Precision Therapeutics

<p><i>PROTACs (proteolysis targeting chimeras) are bifunctional molecules that tag proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins and are on the verge of being clinically used. We now introduce photoswitchable PROTACs that can be activated with the temporal and spatial precision that light provides. These trifunctional molecules, which we named PHOTACs, consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated to varying degrees with different wavelengths of light. Our modular and generalizable approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.</i><b></b></p>

Download Full-text