TL;DR: This research presents a novel and scalable approaches called “Smart Gene Regulation” that allows for real-time annotation of the FISH signal in the Eindhoven–Borff–Seiden cellular automaton.
Abstract: Lech-Gustav Milroy,† Tom N. Grossmann,‡,§ Sven Hennig,‡ Luc Brunsveld,† and Christian Ottmann*,† †Laboratory of Chemical Biology and Institute of Complex Molecular Systems, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands ‡Chemical Genomics Centre of the Max Planck Society, Otto-Hahn Straße 15, 44227 Dortmund, Germany Department of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
Protein−protein interactions (PPIs) are important in almost all biological processes.
The targeting of PPIs will be particularly valuable for diseases that cannot be addressed via "conventional" targets such as enzymes, receptors, or ion channels.
44 By binding to other proteins, 14-3-3 can assist in protein folding, protein localization, and stimulation or inhibition of other PPIs.
14-3-3 proteins from this parasite were shown to play a crucial role in the early stages of the infection by maintaining the host−parasite relationship.
Journal of Medicinal Chemistry
Residues from 14-3-3σ important for binding are shown as labeled sticks; polar contacts are depicted as black dotted lines (PDB ID: 4FL5).
A similar pyridoxal phosphate derivative 15C was reported by Ottmann and co-workers as a 14-3-3 proteinbinding ligand.
■ CONCLUSIONS AND FUTURE DIRECTIONS
The authors demonstrated that 14-3-3 proteins are highly relevant targets in drug discovery and provide a valuable tool in chemical biology.
Importantly, in addition to structural insights on the molecular mechanisms of the different small molecules, in a number of cases the influence on biological pathways has been studied, resulting in promising findings in cell-based model systems relevant to treating a variety of diseases (e.g., Alzheimer's disease, various cancers, asthma, and cystic fibrosis).
The great number of similar binding modes of 14-3-3 PPI partners makes it difficult for small molecule modulation to achieve specificity for one partner over the others.
By studying the "hot spots" responsible for the binding of the two partner proteins in these binary structures, the authors observe that there is a considerable variety of potentially distinct druggable pockets.
They act as molecular glue and thereby provide better opportunities for selectivity.
TL;DR: This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012, and the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide.
Abstract: This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...
TL;DR: Why interactome networks are important to consider in biology, how they can be mapped and integrated with each other, what global properties are starting to emerge from interactome network models, and how these properties may relate to human disease are detailed.
Abstract: Complex biological systems and cellular networks may underlie most genotype to phenotype relationships. Here, we review basic concepts in network biology, discussing different types of interactome networks and the insights that can come from analyzing them. We elaborate on why interactome networks are important to consider in biology, how they can be mapped and integrated with each other, what global properties are starting to emerge from interactome network models, and how these properties may relate to human disease.
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.
834 citations
Cites background from "Modulators of Protein-Protein Inter..."
...Building on the function of natural products, there will also be greater emphasis on synthetic stabilizers of PPIs (Milroy et al., 2014)....
TL;DR: A new classification of peptidomimetics (classes A–D) is introduced that enables a clear assignment of available approaches for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.
Abstract: Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices
TL;DR: A previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation is reported.
487 citations
Cites background from "Modulators of Protein-Protein Inter..."
...In this situation, high-throughput techniques to screen a larger volume of compounds for ternary complex formation, rather than degradation, could be employed (Milroy et al., 2014)....
TL;DR: In this article, a quantenmechanische behandlung des Ubergangs von Elektronenanregungsenergie zwischen gleichartigen Molekulen in Losung gegeben.
Abstract: In Weiterentwicklung fruherer Theorien von J. und F. Perrin und klassischphysikalischer Uberlegungen des Verfassers wird eine quantenmechanische Behandlung des Ubergangs von Elektronenanregungsenergie zwischen gleichartigen Molekulen in Losung gegeben. Der kritische Molekulabstand, unterhalb dessen der ubergang wahrend der Anregungsdauer stattfindet, last sich aus den Absorptions- und Fluoreszenzspektren und der Anregungsdauer der Molekule berechnen. Fur Fluorescein und Chlorophyll a ergeben sich Werte von 50 bzw. 80 AE, entsprechend den mittleren Molekulabstanden in Losungen von 3,2 · 10−3 bzw. 7,7 · 10−4 Molen/Liter. Fur die Bereiche oberhalb und unterhalb der kritischen Konzentration werden Formeln zur Berechnung der Energieabwanderung vom Primarmolekul angegeben, die mit den vorliegenden Messungen der Konzentrationsdepolarisation der Fluoreszenz gut ubereinstimmen. Die Anwendung auf analoge Energiewanderungsprobleme in Molekulkristallen und im Assimilationsapparat der Pflanze wird diskutiert.
TL;DR: This research presents a new probabilistic procedure called ‘spot-spot analysis’ to characterize the response of the immune system to the presence of E.coli.
TL;DR: The relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate is discussed and some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior is described.
Abstract: Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.
Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
TL;DR: This review is an updated and expanded version of the three prior reviews and adds a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixtures" that have now been recognized as drug entities by the FDA and similar organizations.
Abstract: This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74...
Q1. What have the authors contributed in "Modulators of 14-3‐3 protein−protein interactions" ?
Here, the authors aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.
Q2. What topics do he like to explore together with group members and colleagues?
Research topics he likes to dive into together with group members and colleagues include nuclear receptors, protein−protein interactions, synthetic signaling systems, and supramolecular protein assemblies.
Q3. Where did he get his Ph.D. in organic chemistry?
He obtained his Ph.D. in Organic Chemistry from Southampton University under the guidance of Professor Richard Whitby before joining Celltech as a medicinal chemist in 1993.
Q4. What is the role of Carol MacKintosh in the School of Life Sciences?
Carol MacKintosh is Professor of Molecular Signaling in the University of Dundee, where she is also Head of Postgraduate Studies in the School of Life Sciences.