Abstract

Proteins play essential roles in most biological processes, and therefore developing methods of modulating their functions is an important subject that leads to the elucidation of biological mechanisms and the treatment of diseases. The most typical approach is to design a molecule that selectively binds to a target protein. However, this usually requires the structural information of a target protein and is not applicable for proteins whose structure is unidentified. Previously, as “molecular glue”, we have developed a series of water-soluble polymers bearing multiple guanidinium ions.1 Through multivalent salt-bridge interactions, molecular glue tightly adheres to the surface of proteins and can physically block them from interacting with other biomolecules. By this means, we successfully inhibited even proteins whose structural information is unavailable. While the great potential of molecular blue to be a universal tool for protein inhibition has been demonstrated, the non-specific nature of the adhesion is an issue to overcome for practical applications.

This research aims at establishing methodologies to develop, without structural information of target proteins, “affinitive” molecular glues that selectively inhibit them. To achieve this, the possibilities of (1) ligand-guided adhesion2 and (2) combination with molecular imprinting technology3 are investigated. In this symposium, the details and validities of these strategies will be discussed.

Reference:

1. Mogaki, R.; Hashim, P. K.; Okuro, K.; Aida, T. Chem. Soc. Rev. 2017, 46, 6480.
2. Mogaki, R.; Okuro, K.; Aida, T. J. Am. Chem. Soc. 2017, 139, 10072.
3. Belbruno, J. J. Chem. Rev. 2019, 119, 94.