Molecular Glue

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Introduction

Molecular glue is a kind of small chemical molecules that act on the interface between protein and protein. It is a branch of many targeted protein degradation technologies with better medicinal properties, but it is also a difficult one. Molecular glue recognizes and degrades Neo-substrate by modifying the surface of ubiquitin ligase. For example, sulfonamides antineoplastic drug Indisulam, immunomodulatory drugs Thalidomide and Lenalidomide.

Mechanism of Action

Molecular glue is a small molecule that can degrade the target protein by dimerizing the target protein with ubiquitin E3 ligase. This “dimerization degradation” may be caused by the direct binding interaction between E3 ligase and the target protein and the small molecules at the protein-protein interface. Or, the binding of molecular glue leads to the allosteric modification of the protein structure of E3 ligase, which changes the substrate binding site of the enzyme, prevents it from binding to the natural substrate, and enables it to bind to the target protein as a new substrate. The formation of a ternary complex containing E3 ligase, target protein and small molecules leads to ubiquitination of the target protein, triggering its destruction by proteasome. After the ubiquitin step, the molecular glue is dissociated and released to form a new protein complex. Therefore, the catalytic mode of molecular glue is similar to that of PROTAC^® degrader.

Application

We need new drugs because there are still many diseases that cannot be treated by traditional small molecule therapy. The popular method in recent history is to use small molecules to break down protein-protein interactions. This method is effective, but researchers have learned that it applies only to proteins with special functions. It turns out that many disease-related proteins do not have these special functions. The molecular glue with the function of protein pairing provides another option: gather proteins together and carry out new protein-protein interactions to disrupt the biology of the disease. For example, Immunomodulatory imide drugs (IMiDs) is used in medicine to treat hematological cancers, especially multiple myeloma, and its potential in the treatment of autoimmune diseases such as systemic lupus erythematosus is being studied.

References:

1. Mogaki, R., Okuro, K., Ueki, R., Sando, S., & Aida, T. (2019). Molecular Glue that Spatiotemporally Turns on Protein–Protein Interactions. Journal of the American Chemical Society, 141(20), 8035-8040.
2. Akinjiyan, F. A., Carbonneau, S., & Ross, N. T. (2017). Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system. Bioorganic & Medicinal Chemistry Letters, 27(20), 4589-4596.
3. Isobe, Y., Okumura, M., McGregor, L. M., Brittain, S. M., Jones, M. D., Liang, X., ... & Schirle, M. (2020). Manumycin polyketides act as molecular glues between UBR7 and P53. Nature chemical biology, 16(11), 1189-1198.

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