Stabilization of Protein–Protein Interactions in chemical biology and drug discovery

More than 300,000 Protein–Protein Interactions (PPIs) can be found in human cells. This number is significantly larger than the number of single proteins, which are the classical targets for pharmacological intervention. Hence, specific and potent modulation of PPIs by small, drug-like molecules wou...

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Vydáno v:Progress in biophysics and molecular biology Ročník 119; číslo 1; s. 10 - 19
Hlavní autoři: Bier, David, Thiel, Philipp, Briels, Jeroen, Ottmann, Christian
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Elsevier Ltd 01.10.2015
Témata:
Biological Products - pharmacology
Drug Discovery - methods
Humans
Interface stabilization
Natural products
Protein Interaction Maps - drug effects
Protein-ligand interaction
Proteins - chemistry
Proteins - metabolism
Small molecules
X-ray crystallography
X-ray crystallography
Small molecules
Natural products
Protein-ligand interaction
Interface stabilization
ISSN:0079-6107, 1873-1732, 1873-1732
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Shrnutí:More than 300,000 Protein–Protein Interactions (PPIs) can be found in human cells. This number is significantly larger than the number of single proteins, which are the classical targets for pharmacological intervention. Hence, specific and potent modulation of PPIs by small, drug-like molecules would tremendously enlarge the “druggable genome” enabling novel ways of drug discovery for essentially every human disease. This strategy is especially promising in diseases with difficult targets like intrinsically disordered proteins or transcription factors, for example neurodegeneration or metabolic diseases. Whereas the potential of PPI modulation has been recognized in terms of the development of inhibitors that disrupt or prevent a binary protein complex, the opposite (or complementary) strategy to stabilize PPIs has not yet been realized in a systematic manner. This fact is rather surprising given the number of impressive natural product examples that confer their activity by stabilizing specific PPIs. In addition, in recent years more and more examples of synthetic molecules are being published that work as PPI stabilizers, despite the fact that in the majority they initially have not been designed as such. Here, we describe examples from both the natural products as well as the synthetic molecules advocating for a stronger consideration of the PPI stabilization approach in chemical biology and drug discovery.
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ISSN:0079-6107
1873-1732
1873-1732
DOI:10.1016/j.pbiomolbio.2015.05.002