Molecular glue
Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems.
Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways.
[2] CsA, discovered in 1971 during routine screening for antifungal antibiotics, exhibited immunosuppressive properties by inhibiting the peptidyl–prolyl isomerase activity of cyclophilin, ultimately preventing organ transplant rejections.
[3] The term molecular glue found its way into publications in 1992, highlighting the selective gluing of specific proteins by antigenic peptides, akin to immunosuppressants acting as docking assemblies.
[3] Rimiducid, a purposefully synthesized molecular glue, demonstrated its effectiveness in eliminating graft-versus-host disease by inducing dimerization of death-receptor fusion targets.
[6] The term “molecular glue” has since been used, particularly in the context of targeted protein degradation, to specifically describe monovalent compounds with drug-like properties capable of promoting productive protein-protein interactions, instead of CIPs in general.
[8] The transformative power of molecular glues in medicine became evident as drugs like sandimmune, tacrolimus, sirolimus, thalidomide, lenalidomide, and taxotere proved effective.
[9] In the current era, molecular glues have become a more commonly utilized approach for targeted protein degradation, offering advantages over traditional small molecule drugs and PROTACs.
A recent study reported the identification and rational design of potent small molecules acting as molecular glues to enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCFβ-TrCP.
Unlike PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, optimizing contacts for both the substrate and ligase within a single molecular entity.
[10] In contrast, PROTACs face challenges such as high molecular weight, poor cell permeability, and unfavorable pharmacokinetic characteristics, hindering their clinical development.
[11] The identification of molecular-glue-type degraders has typically occurred retrospectively and serendipitously, but recent chemical-profiling approaches aim to prospectively identify small molecules acting as molecular glues.
[16] Additionally, the versatility of small-molecule molecular glue compounds in targeting various proteins implicated in disease mechanisms provides a valuable avenue for unraveling the complexities of neurodegenerative disorders.
This unique approach can lead to prolonged pharmacodynamic efficacy with lower pharmacokinetic exposure, potentially reducing toxicity and the risk of antiviral resistance.
[17] Molecular glue serves as a valuable tool in chemical biology, enabling scientists to manipulate and understand protein functions and interactions in a controlled manner.
[17] The ability of small-molecule molecular glue compounds to induce iterative cycles of target degradation provides researchers with a powerful method for studying protein-protein interactions and opens avenues for drug development in various human diseases.
With an expanding understanding of protein-protein interactions, molecular glue holds significant promise across biology, medicine, and chemistry, potentially revolutionizing cellular processes and advancing innovative disease treatments.
