Targeted protein degradation is an emerging therapeutic strategy that leverages the cell’s natural protein clearance pathways to eliminate proteins of interest (POIs). One common approach involves bif...

Ligand discovery of nonenzymatic proteins can be accomplished through screening methods utilizing libraries comprising small molecules, peptides, and peptidomimetics. Incorporating peptoids, which are...

The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.

Regulators of G protein signaling (RGS) proteins negatively regulate signaling through G protein-coupled receptors, and reduced RGS protein function i…

IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or...

Immunoproteasome (iCP) is a proteasome isoform that is expressed under inflammatory conditions such as cytokine interferon-γ exposure. The iCP has different catalytic subunits other than the standard CP (standard core particle), allowing the production of major histocompatibility complex class I (MHC-I) compatible peptides for eventual T-cell activation. We have previously reported the design of a fluorescent probe that monitors iCP activity in cells called TBZ-1, and we applied TBZ-1’s iCP recognition sequence for prodrug release into iCP-active cells. Here, we demonstrate a proof-of-concept of the iCP as a prodrug release enzyme. The “payload” we utilized was a toxic moiety, doxorubicin, and a degrader for transcription factor, BRD4. Both examples show that iCP activity is required to elicit cell death or degradation of BRD4. This report highlights that the iCP is a viable prodrug target, and its activity can be used to release a variety of cargo in cells expressing the iCP.

National Institutes of Health grants generated almost $95 billion in economic activity nationwide in FY 2024 according to a new report by United for Medical Research.

Microbial infections lead to drastic changes in the architecture and metabolism of the host cell. The inaugural FEBS EMBO Cell Biology of Host-Pathogen Interaction Advanced Course explores the mechan…

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These inventors, educators, and unsung heroes changed lives through their work in chemistry

The Arthur C. Cope Postdoctoral Fellowship (CPF) of the American Chemical Society (ACS) is a two-year postdoctoral fellowship awarded yearly to Ph.D. candidates or postdoctoral researchers within their first two years of pursuing postdoctoral research in organic chemistry.

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The Graduate Research Symposium (GRS) provides opportunities for graduate students in organic chemistry to interact with leaders in the field.

Degrons are short amino acids sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with...

The ONX-0914-alkyne probe described here allows for the conjugation to a variety of fluorophores through click chemistry. It can then be used to visualize immunoproteasome activity in gel-based, micr....