title: Stabilization of Protein-Protein Interactions in chemical biology and drug discovery.
abstract: 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.
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands; Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117 Essen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bier
authors.affiliation: Applied Bioinformatics, Center for Bioinformatics, and Dept. of Computer Science, University of Tübingen, Sand 14, 72076 Tübingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Thiel
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands; Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117 Essen, Germany.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Briels
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands; Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117 Essen, Germany. Electronic address: c.ottmann@tue.nl.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
mesh_terms: D001688:Biological Products / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D060066:Protein Interaction Maps / Q000187:drug effects*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D001688:Biological Products; D011506:Proteins
keywords: Interface stabilization; Natural products; Protein-ligand interaction; Small molecules; X-ray crystallography