Journal ArticleDOI
Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers.
Eline Sijbesma,K.K. Hallenbeck,Seppe Leysen,P.J. de Vink,Lukasz Skora,Wolfgang Jahnke,Luc Brunsveld,Michelle R. Arkin,Christian Ottmann +8 more
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TLDR
This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery by identifying orthosteric stabilizers that increase 14-3-3/ERα affinity up to 40-fold and proposing the mechanism of stabilization based on X-ray crystal structures.Abstract:
Modulation of protein–protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3σ and a peptide derived from Estrogen Receptor α (ERα), an important breast cancer target that is negatively regulated by 14-3-3σ. We identify orthosteric stabilizers that increase 14-3-3/ERα affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERα-like motifs over other representative 14-3-3 clients. This fi...read more
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Journal ArticleDOI
Unifying principles of bifunctional, proximity-inducing small molecules
TL;DR: The chemical and biophysical principles common to all bifunctional, proximity-inducing small molecules are described and the underappreciated diversity of their chemical structures and biological mechanisms are discussed.
Journal ArticleDOI
Visualizing and trapping transient oligomers in amyloid assembly pathways.
TL;DR: Use of methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods, and mass spectrometry, and chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states are discussed.
Journal ArticleDOI
Overview of Recent Strategic Advances in Medicinal Chemistry
Gaochan Wu,Tong Zhao,Dongwei Kang,Jian Zhang,Yu'ning Song,Vigneshwaran Namasivayam,Jacob Kongsted,Christophe Pannecouque,Erik De Clercq,Vasanthanathan Poongavanam,Xinyong Liu,Peng Zhan +11 more
TL;DR: This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.
Journal ArticleDOI
Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design
Shan-Meng Lin,Shih-Chao Lin,Jia-Ning Hsu,Chung-ke Chang,Ching-Ming Chien,Yong Sheng Wang,Hung-Yi Wu,U-Ser Jeng,Kylene Kehn-Hall,Ming-Hon Hou +9 more
TL;DR: 5-benzyloxygramine is identified as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities, and could be applied toward drug discovery against CoV diseases.
Journal ArticleDOI
Bifunctional chemical probes inducing protein-protein interactions.
Chiara Maniaci,Alessio Ciulli +1 more
TL;DR: This review highlights progress over the past three years on recruitment to E3 ubiquitin ligases by 'molecular glues' and chimeric dimerizers (PROTACs) for targeted protein degradation, and promises to significantly expand the range of tractable targets for chemical biology and therapeutic intervention.
References
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Journal ArticleDOI
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
TL;DR: These studies discovered small molecules that bind with drug-like potencies to 'hotspots' on the contact surfaces involved in protein–protein interactions, and bind with much higher efficiencies than do the contact atoms of the natural protein partner.
Journal ArticleDOI
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
TL;DR: The development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C) and structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner are provided.
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Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.
TL;DR: The past 20 years have seen many advances in understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets.
Journal ArticleDOI
Small molecules, big targets: drug discovery faces the protein–protein interaction challenge
TL;DR: The research leading to breakthroughs in PPI inhibition is described and the existence of groups of structurally related PPIs within the PPI target class is highlighted to illustrate the research strategies that have proved most useful.
Journal ArticleDOI
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade
Christine Bulawa,Stephen Connelly,Michael Devit,Lan Wang,Charlotte Weigel,James Fleming,Jeff Packman,Evan T. Powers,R. Luke Wiseman,Ted R. Foss,Ian A. Wilson,Jeffery W. Kelly,Richard Labaudinière +12 more
TL;DR: The molecular and structural basis of TTR tetramer stabilization by tafamidis is described, suggesting that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.