Transformative Potential of 'Molecular Glues' in Precision Medicine

University of Minnesota researchers report intracellular "molecular glues" and "molecular bumpers" that rewire GPCR signaling toward pathway-selective outcomes, creating a plausible route to precision therapeutics with fewer off-target effects and highlighting intracellular allosteric sites as druggable nodes.

Experimentally, structural and biochemical mapping paired with cell-based signaling assays demonstrated intracellular engagement and pathway-selective signaling shifts. Binding and structural studies were linked to G protein versus β-arrestin functional readouts and compounds described as molecular bumpers showed directionally biased activity, preserving particular G protein subtype signaling while selectively blocking β-arrestin recruitment.

Mechanistically, glues recruit or stabilize specific intracellular partners while bumpers sterically block partner engagement, altering effector coupling without engaging the orthosteric site. By contrast, orthosteric ligands typically change receptor activation more uniformly, blending therapeutic and adverse signaling. That distinction suggests a means to improve therapeutic index by sculpting downstream signaling rather than relying solely on receptor occupancy.

Immediate translational targets include the opioid receptor family, dopamine receptors, and indications tied to pain and addiction.