Chemical control over protein-protein interactions: beyond inhibitors.
Protein-protein interactions have become attractive drug targets and recent studies suggest that these interfaces may be amenable to inhibition by small molecules. However, blocking specific interactions may not be the only way of manipulating the extensive network of interacting proteins. Recently, several approaches have emerged for promoting these interactions rather than inhibiting them. Typically, these strategies employ a bifunctional ligand to simultaneously bind two targets, forcing their juxtaposition. Chemically "riveting" specific protein contacts can reveal important aspects of regulation, such as the consequences of stable dimerization or the effects of prolonged dwell time. Moreover, in some cases, entirely new functions arise when two proteins, which normally do not interact, are brought into close proximity with one another. Together with inhibitors, bifunctional molecules are part of a growing toolbox of chemical probes that can be used to reversibly and selectively control the interact-ome. Using these reagents, new insights into the dynamics of protein-protein interactions and their importance in biology are beginning to emerge. Future hurdles in this area lie in the development of robust synthetic platforms for rapidly generating compounds to meet the challenges of diverse protein-protein interfaces.
Department of Pathology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA. gestwick@umich.edu
Jason E
JE
Gestwicki
Paul S
PS
Marinec
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D024921:Drug Resistance, Multiple, Viral; D008024:Ligands; D008958:Models, Molecular; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D015202:Protein Engineering; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D020123:Sirolimus / Q000737:chemistry / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology; D016559:Tacrolimus / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008024:Ligands; D009479:Neuropeptides; D011506:Proteins; D020123:Sirolimus; D016559:Tacrolimus