Knitting and untying the protein network: modulation of protein ensembles as a therapeutic strategy

Abstract

Proteins constitute the working machinery and structural support of all organisms. In performing a given function, they must adopt highly specific structures that can change with their level of activity, often through the direct or indirect action of other proteins. Indeed, proteins typically function within an ensemble, rather than individually. Hence, they must be sufficiently flexible to interact with each other and execute diverse tasks. The discovery that errors within these groups can ultimately cause disease has led to a paradigm shift in drug discovery, from an emphasis on single protein targets to a holistic approach whereby entire ensembles are targeted.

Figure 1

Yeast protein interaction network map. (Reprinted by permission from Macmillan Publishers Ltd. Science, 411: 41–42, © 2001).

Figure 2

A: Pentavalent saccharide-inhibitor for the receptor binding site of cholera toxin B-pentamer; at the right, a schematic representation of the ligand binding mode (Ref.80). B: Porphyrin-based tetravalent ligand for blocking human K_v1.3 potassium channel; at the bottom, the complex protein-ligand (Reproduced from Ref., with permission from the American Chemical Society, USA, © 2003).

Figure 3

A: Bistrazine compound that inhibits the tetrameric assembly of RS virus fusion protein. B: Cu²⁺-IDA-containing trivalent ligand that targets the imidazole side-chain of three histidines at the surface of carbonic anhydrase. C: Calixarene-based ligand functionalized with multiple recognition elements designed for disrupting the interaction of the homodimer PDGF with its receptor. D: [Rb(bpy)₃] complex for positively charged cytochrome c surface recognition.

Figure 4

Pharmacoperones in action: a misfolded protein imported to the ER can be rapidly removed by the quality control system, in order to avoid it being crushed into toxic aggregates. An exogenous chaperone (the pharmacoperone) can act as a template and aid the protein to fold correctly. Once properly folded, the protein can bypass the quality control system and travel to its final location, where it can perform its function. In contrast to endogenous molecular chaperones, pharmacological chaperones remain associated once the protein has been folded. In the example illustrated here, a mutated receptor is rescued by an inhibitor (the pharmacoperone) which is then displaced by the endogenous natural ligand.

Figure 5

Protein p53. A: Simplified scheme of the p53 pathway. B: SAXS models of free p53; the structured core DNA binding domain (green and blue) and tetramerization domain (red) are displayed in cartoon representation, and unstructured connector linkers (grey), N-termini (salmon) and C-termini (yellow) in semitransparent space-fill mode (Reproduced from Ref., © 2007 National Academy of Science, USA).