{"id":679680,"date":"2025-07-12T15:15:17","date_gmt":"2025-07-12T12:15:17","guid":{"rendered":"https:\/\/buradabiliyorum.com\/en\/data-mining-uncovers-treasure-trove-of-previously-untouchable-proteins-for-drug-development\/"},"modified":"2025-07-12T15:15:17","modified_gmt":"2025-07-12T12:15:17","slug":"data-mining-uncovers-treasure-trove-of-previously-untouchable-proteins-for-drug-development","status":"publish","type":"post","link":"https:\/\/buradabiliyorum.com\/en\/data-mining-uncovers-treasure-trove-of-previously-untouchable-proteins-for-drug-development\/","title":{"rendered":"Data mining uncovers treasure-trove of previously ‘untouchable’ proteins for drug development"},"content":{"rendered":"
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\n Toggle information panel CRBN target space expansion within and beyond G-loops. MGDs are small-molecule compounds that recruit target proteins to CRBN through a general<\/a>izable G-loop recognition motif. Computational matchmaking algorithms using structural G-loop templates predict >1600 human proteins with surface-exposed and CRBN-compatible \u03b2-hairpin or helical G-loop motifs. Surface-based mimicry searches overcome the G-loop paradigm and provide opportunities to expand the CRBN target space beyond G-loop degrons. Credit: Science<\/a><\/i> (2025). DOI: DOI: 10.1126\/science.adt6736
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Molecular glues, tiny molecules that connect one protein to another, are promising targets for pharmaceutical research. By linking a disease-related protein to one that triggers a cell’s demolition and recycling pathways, pharmaceutical researchers have been able to develop novel therapies for otherwise drug-resistant diseases.<\/p>\n

It was thought, however, that this app<\/a>roach to drug development was limited to only those proteins that had a specific surface feature called a beta-hairpin loop motif.<\/p>\n

Expanding on this once-narrow discovery space, new research published<\/a> in the journal Science<\/i> has uncovered a vastly wider array of protein surface features capable of binding with a molecular glue degrader (a pharmaceutical version of a molecular glue molecule). These results may open new pathways for treating diseases by targeting proteins previously thought to be ‘untouchable’ to drug therapies.<\/p>\n

Molecular glue degraders function by first latching onto a protein called Cereblon, which is part of the cell’s protein-recycling process. The molecular glue degrader then induces small changes to the surface of the Cereblon protein, essentially creating a docking site for otherwise inaccessible target protein. Once connected, Cereblon tags the protein with a molecule called E3 ubiquitin ligase, which cues the cell to dismantle the protein.<\/p>\n

The researchers began by computationally searching the human proteome (protein’s version of the genome) for features that might be a good-enough match for a prototypical molecular glue receptor. This initially uncovered 1633 human proteins that, because of a loop-like motif on their surfaces, might be compatible with Cereblon.<\/p>\n

This mining approach not only identified beta-hairpin loops in human proteome but also uncovered helical loops, which are a structurally distinct but sufficient compatible recognition motif.<\/p>\n

Among their findings, the research identified VAV1, a protein previously inaccessible to drugs that has broad therapeutic potential in autoimmune and chronic inflammatory disease.<\/p>\n

The researchers write: “Our systematic exploration of the CRBN [Cereblon] target space unveils an extraordinary plasticity of CRBN, redefines rules for target engagement, and provides opportunities for target space expansion within and beyond the beta-hairpin G-loop paradigm.”<\/p>\n

It bears noting that the drug thalidomide was later discovered to act as a molecular glue degrader. Though pulled from the market in the 1960s due to its devastating side effects when taken during pregnancy, it has since seen a resurgence for its ability to treat a type of cancer and is an effective therapy for inflammation in patients with Hansen’s disease.<\/p>\n

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\n Written for you by our author Charles Blue<\/a>,
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More information:<\/strong>
\n\t\t\t\t\t\t\t\t\t\t\t\tGeorg Petzold et al, Mining the CRBN target space redefines rules for molecular glue\u2013induced neosubstrate recognition, Science<\/i> (2025). DOI: 10.1126\/science.adt6736<\/a>\n<\/p>\n

Marcus D. Hartmann, Expanding the reach of molecular glue degraders, Science<\/i> (2025). DOI: 10.1126\/science.ady4446<\/a><\/p>\n<\/p><\/div>\n

\n\t\t\t\t\t\t\t\t\t\t\t\t \u00a9 2025 Science X Network\n\t\t\t\t\t\t\t\t\t\t\t <\/p>\n

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\n\t\t\t\t\t\t\t\t\t\t\t\tCitation<\/strong>:
\n\t\t\t\t\t\t\t\t\t\t\t\tData mining uncovers treasure-trove of previously ‘untouchable’ proteins for drug development (2025, July 12)
\n\t\t\t\t\t\t\t\t\t\t\t\tretrieved 12 July 2025
\n\t\t\t\t\t\t\t\t\t\t\t\tfrom https:\/\/phys.org\/news<\/a>\/2025-07-uncovers-treasure-trove-previously-untouchable.html\n\t\t\t\t\t\t\t\t\t\t\t <\/p>\n

\n\t\t\t\t\t\t\t\t\t\t\t This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
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