Supramolecular Chemistry Targeting Proteins

Abstract

The specific recognition of protein surface elements is a fundamental challenge in the life sciences. New developments in this field will form the basis of advanced therapeutic approaches and lead to applications such as sensors, affinity tags, immobilization techniques, and protein-based materials. Synthetic supramolecular molecules and materials are creating new opportunities for protein recognition that are orthogonal to classical small molecule and protein-based approaches. As outlined here, their unique molecular features enable the recognition of amino acids, peptides, and even whole protein surfaces, which can be applied to the modulation and assembly of proteins. We believe that structural insights into these processes are of great value for the further development of this field and have therefore focused this Perspective on contributions that provide such structural data.

Protein Recognition by Functionalized Sulfonatocalix[4]arenes

“…These studies have demonstrated the breadth of chemical functionalities that can be matched with structural features on protein surfaces. In some cases, the binding of a supramolecular ligand leads to protein assembly . Such a “molecular glue” property has applications in the fabrication of advanced materials …”

Cucurbit[7]uril‐Dimethyllysine Recognition in a Model Protein

“…[15,16,[19][20][21] Supramolecular building blocks are increasingly popular as receptors for protein binding and assembly. [12][13][14] Examples include protein oligomerization mediated by calixarenes [16] and foldamers. [17] Anionic calixarenes have proven particularly useful for the assembly of cationic proteins.…”

Generation of Dynamic Combinatorial Libraries Using Hydrazone‐Functionalized Surface Mimetics

“…A central goal in supramolecular chemical biology1 is to generate ligands capable of solvent exposed protein‐surface recognition for the purpose of orthosteric protein–protein interaction (PPI) inhibition 2, 3, 4. Inhibition of PPIs is considered challenging in view of the fact that such interactions involve extended and less well‐defined surfaces than the “lock‐and‐key”‐like interfaces that have historically proven to be tractable targets for drug‐discovery 4.…”

“…A central goal in supramolecular chemical biology [1] is to generate ligands capable of solvent exposed protein-surface recognition for the purpose of orthosteric protein-protein interaction (PPI) inhibition. [2][3][4] Inhibition of PPIs is considered challenging in view of the fact that such interactions involve extended and less well-defined surfaces than the "lock-and-key"like interfaces that have historically proven to be tractable targets for drug-discovery. [4] Several supramolecular scaffolds have been explored as templates upon which to elaborate ligands for selective and high affinity protein-surface binding, [5] including: porphyrins, [6][7][8][9] calixarenes, [9][10][11][12][13] cucurbiturils, [14,15] molecular clips, [16,17] ruthenium(II) tris-chelates [18][19][20][21][22][23] and other ligands.…”