Discover New ‘Molecular Glues’ as a Possible Therapeutic Approach for Autoimmune Conditions

Good news! Amazing stuff!

"“Molecular glues are an exciting new area of research that allows us to fight disease by working with the body’s systems rather than against them.”  ... “By gluing together an inactive form of the BRISC complex with our system, we’re able to reduce the continuous inflammatory signaling due to dysregulated BRISC complex activity in autoimmune diseases.”

Deubiquitylases, or DUBs, are enzymes that regulate protein stability; A DUB removes the “ubiquitin mark” on a protein, normally targeting it for degradation, thereby stabilizing the protein resulting in aberrant signaling.

Certain diseases, such as lupus, are due to aberrant inflammatory signaling. Approaches targeting this dysregulated DUB activity are expected to balance protein homeostasis and lead to pathogenic outcomes. Scientists are interested in methods that could therapeutically intervene to reduce DUB dysregulation and its pathogenic effects; however, until now, targeting DUB dysregulation has been challenging with small-molecule approaches due to lack of specificity and side effects. ...

a different approach to overcoming the challenge with a new technology termed Molecular Glue. Unlike inhibitory small molecules, which block the active processing site of an enzyme, molecular glues facilitate the formation of protein complexes. In this paper, the research team applied the molecular glue approach, for the first time, to form an inactive complex against pathological inflammatory signaling due to aberrant DUB activity.

A DUB in humans called BRISC complex regulates inflammatory signaling. When BRISC becomes dysregulated, excessive inflammation can flare up, and research suggests that BRISC dysregulation contributes to the persistent inflammation in autoimmune conditions like lupus.

After an initial high-throughput screen, ... identified compounds that functioned as molecular glues that selectively stabilize BRISC in a biologically inactive complex, which they confirmed with high-resolution cryo-electron microscopy and mass spectrometry. The BRISC molecular glues, or BLUEs, bind to BRISC in a way that causes it to form an inactive complex. The BLUE-induced inactive BRISC complex can no longer stabilize inflammatory signaling, caused by aberrant BRISC activity. The deactivated complex allows the ubiquitinated inflammatory signaling protein to be degraded under normal protein homeostasis conditions.

In preclinical testing, the researchers confirmed that the BLUEs were successful in reducing interferon signaling (a potent inflammatory response). This finding was particularly notable for reducing interferon signaling in blood samples from patients with scleroderma, an autoimmune disease in which interferon responses are abnormally elevated. ..."

From the abstract:

"Deubiquitylases (DUBs) are crucial in cell signaling and are often regulated by interactions within protein complexes.

The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signaling by cleaving K63-linked polyubiquitin chains on type I interferon receptors (IFNAR1).

As a Zn2+-dependent JAMM/MPN (JAB1, MOV34, MPR1, Pad1 N-terminal) DUB, BRCC36 is challenging to target with selective inhibitors.

Here, we discover first-in-class inhibitors, termed BRISC molecular glues (BLUEs), which stabilize a 16-subunit human BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit, serine hydroxymethyltransferase 2.

This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs.

BLUE treatment reduced interferon-stimulated gene expression in cells containing wild-type BRISC and this effect was abolished when using structure-guided, inhibitor-resistant BRISC mutants.

Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential strategy to mitigate type I interferon-mediated diseases.

Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting rather than blocking protein–protein interactions."

The Wistar Institute, The University of Leeds, and the Perelman School of Medicine Discover New ‘Molecular Glues’ as a Possible Therapeutic Approach for Autoimmune Conditions - The Wistar Institute "The Collaborative Discovery Could Help Mitigate Inflammation in Autoimmune Diseases"

Molecular glues that inhibit deubiquitylase activity and inflammatory signaling (open access)

Fig. 7: Proposed model of BLUE compound mode of action.