Stabilization and inhibition of protein-protein interactions: the 14-3-3 case study

Small-molecule modulation of protein-protein interactions (PPIs) is one of the most exciting but also difficult fields in chemical biology and drug development. As one of the most important "hub" proteins with at least 200-300 interaction partners, the 14-3-3 proteins are an especially fru...

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Bibliographic Details
Published in:ACS chemical biology Vol. 8; no. 1; p. 27
Main Authors: Milroy, Lech-Gustav, Brunsveld, Luc, Ottmann, Christian
Format: Journal Article
Language:English
Published: United States 18.01.2013
Subjects:
14-3-3 Proteins - antagonists & inhibitors
14-3-3 Proteins - metabolism
Diterpenes - chemistry
Diterpenes - pharmacology
Glycosides - chemistry
Glycosides - pharmacology
Humans
Models, Molecular
Protein Binding
Protein Stability - drug effects
ISSN:1554-8937, 1554-8937
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Summary:Small-molecule modulation of protein-protein interactions (PPIs) is one of the most exciting but also difficult fields in chemical biology and drug development. As one of the most important "hub" proteins with at least 200-300 interaction partners, the 14-3-3 proteins are an especially fruitful case for PPI intervention. Here, we summarize recent success stories in small-molecule modulation, both inhibition and stabilization, of 14-3-3 PPIs. The chemical breath of modulators includes natural products such as fusicoccin A and derivatives but also compounds identified via high-throughput and in silico screening, which has yielded a toolbox of useful inhibitors and stabilizers for this interesting class of adapter proteins. Protein-protein interactions (PPIs) are involved in almost all biological processes, with any given protein typically engaged in complexes with other proteins for the majority of its lifetime. Hence, proteins function not simply as single, isolated entities but display their roles by interacting with other cellular components. These different interaction patterns are presumably as important as the intrinsic biochemical activity status of the protein itself. The biological role of a protein is therefore decisively dependent on the underlying PPI network that furthermore can show great spatial and temporal variations. A thorough appreciation and understanding of this concept and its regulation mechanisms could help to develop new therapeutic agents and concepts.
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ISSN:1554-8937
1554-8937
DOI:10.1021/cb300599t