(Far left) Wistar's medicinal chemist Dr. Joe Salvino in the lab
PHILADELPHIA — (April 14, 2025) —The Wistar Institute’s — in collaboration with of The University of Leeds and of The Perelman School of Medicine at the University of Pennsylvania — has discovered a type of “molecular glue” that can be used to inhibit certain pathological protein interactions. Their findings were published in the paper, “” from Nature Structural & Molecular Biology.
“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.” said Dr. Salvino, Wistar professor. “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.
Salvino and his colleagues took 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, Salvino and his co-authors 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.
“One of the difficulties in drug development is that some ideal targets don’t have a clearly defined druggable site. This makes it incredibly difficult to design drugs against, because there’s nowhere for a drug molecule to attach itself to stop rogue activity. So, we need to find another way,” said Dr. Elton Zeqiraj, lead author, explaining his rationale for molecular glue design.
As Penn’s Dr. Roger Greenberg said, “Our approach allows us to fight inflammation by working with molecules rather than against them. By gluing BRISC shut, we’ve demonstrated a possible effective therapy for autoimmune conditions; I’m looking forward to seeing how our BLUE design can be used to develop possible treatments.”
Authors: Francesca Chandler1, Poli Adi Narayana Reddy2, Smita Bhutda3, Rebecca L. Ross4, 5, Arindam Datta3, Miriam Walden1, Kieran Walker4, Stefano Di Donato4, 5, Joel A. Cassel2, Michael A. Prakesch6, Ahmed Aman6, 7, Alessandro Datti8, Lisa J. Campbell1, Martina Foglizzo1, Lillie Bell1, Daniel N. Stein3, James R. Ault1, Rima S. Al-awar6, 9, Antonio N. Calabrese1, Frank Sicheri10, 11, 12, Francesco Del Galdo4, 5, Joseph M. Salvino2, Roger A. Greenberg3 and Elton Zeqiraj1
1Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds
2Molecular Screening & Protein Expression Facility, The Wistar Institute
3Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine
4Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and
Health, University of Leeds
5NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals, NHS Trust,
Chapel Allerton Hospital
6Drug Discovery Program, Ontario Institute for Cancer Research
7Leslie Dan Faculty of Pharmacy, University of Toronto
8Department of Agriculture, Food, and Environmental Sciences, University of Perugia
9Department of Pharmacology and Toxicology, University of Toronto
10Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health
System
11Department of Molecular Genetics, University of Toronto
12Department of Biochemistry, University of Toronto
Work supported by: The Wellcome Trust PhD studentship; the Wellcome Trust Senior Fellowship; the UKRI-MRC grant; the Basser External Research Grant; the Lupus Research Alliance Target in Lupus Grant; NIH grants S10OD030245-01, R01 CA138835, and P30 CA010815-53; Medical Research Council Confidence in Concept Grant 121999; Wellcome iTPA funds 120972; the Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society; the University of Leeds ABSL award; and the MRC World Class Labs award. Additional funding provided by the Wellcome Trust; the North American Foundation for The University of Leeds; Biotechnology and Biological Sciences Research Council; Waters UK.
Publication information: “Molecular glues that inhibit deubiquitylase activity and inflammatory signaling” from Nature Structural & Molecular Biology
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The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. .
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