Carborane–β-cyclodextrin complexes as a supramolecular connector for bioactive surfaces

Supramolecular chemistry provides an attractive entry to generate dynamic and well-controlled bioactive surfaces. Novel host–guest systems are urgently needed to provide a broader affinity and applicability portfolio. A synthetic strategy to carborane–peptide bioconjugates was therefore developed to provide an entry to monovalent supramolecular functionalization of β-cyclodextrin coated surfaces. The β-cyclodextrin·carborane–cRGD surfaces are formed efficiently and with high affinity as demonstrated by IR-RAS, WCA, and QCM-D, compare favourable to existing bio-active host–guest surface assemblies, and display an efficient bioactivity, as illustrated by a strong functional effect of the supramolecular system on the cell adhesion and spreading properties. Cells seeded on the supramolecular surface displaying bioactive peptide epitopes exhibited a more elongated morphology, focal adhesions, and stronger cell adhesion compared to control surfaces. This highlights the macroscopic functionality of the novel supramolecular immobilization strategy

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p

Stabilization of protein-protein interactions in drug discovery

Introduction: PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.</p

Pharmaceutical implications of helix length control in helix-mediated protein-protein interactions

The most abundant protein secondary structure in nature – the a-helix – is frequently found at protein interfaces, making it an important lead structure for the design of small-molecule modulators of protein–protein interactions (PPIs). Nature’s ability to precisely control the length of a-helices, especially in the context of helix-mediated PPIs, is key to ensuring the optimal interaction of protein partners. By extension, precise control over the length of a-helix mimetics is necessary to ensure optimal disruption of a-helix-mediated PPIs. This article will highlight the emerging importance of helix length control in the context of helix-mediated PPIs through a discussion of the contemporary chemical approaches to identifying novel helix mimetic inhibitors, including all-hydrocarbon stapling, hydrogen bond surrogates and optimized peptides emerging from in vitro screening methods. A current update on the therapeutic status of the different approaches is provided, as well as indications as to their long-term potential

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 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

Targeting alpha-helix based protein interactions : nuclear receptors as a case study

This book chapter highlights the important role played by a-helical structures in controlling protein-protein interactions (PPIs). First a brief discussion of the fundamental aspects of the a-helix structure is provided, including a word on nomenclature. Then some examples of different proteins involved in a-helical PPIs – for example Bcl-2, p53 and HIF-1a– are introduced alongside current methods for inhibiting these interactions, which typically rely on small lipophilic drug molecules, oligomeric structures or modified peptides. Next, nuclear hormone receptors will be discussed as quintessential a-helix mediated PPIs. By covering two of the most widely studied members of this intriguing protein class – the estrogen receptor (ER) and the androgen receptor (AR)– the important structural features of nuclear receptors will be discussed, and the significance of PPIs in terms of the binding of a-helical coregulator proteins highlighted. Finally, the chapter will round off with a discussion on how the principles of a-helicity have helped in the design of peptide-based and non-peptidic inhibitors of PPIs for drug discovery. In this case, the reader's attention will be mainly drawn to recent advances in the field

Strong supramolecular control over protein self-assembly using a polyamine decorated β-cyclodextrin as synthetic recognition element

The supramolecular host molecule heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-ß-cyclodextrin provides strong control over protein self-assembly in synthetic supramolecular protein constructs. Mono-functionalization of this modified ß-cyclodextrin with a cysteine residue allows for site-selective synthetic conjugation to a protein and formation of a highly stable synthetic protein complex with a lithocholic acid conjugated protein as the interaction partner

Dual-input regulation and positional control in hybrid oligonucleotide/discotic supramolecular wires

The combination of oligonucleotides and synthetic supramolecular systems allows for novel and long-needed modes of regulation of the self-assembly of both molecular elements. Discotic molecules were conjugated with short oligonucleotides and their assembly into responsive supramolecular wires studied. The self-assembly of the discotic molecules provides additional stability for DNA-duplex formation owing to a cooperative effect. The appended oligonucleotides allow for positional control of the discotic elements within the supramolecular wire. The programmed assembly of these hybrid architectures can be modulated through the DNA, for example, by changing the number of base pairs or salt concentration, and through the discotic platform by the addition of discotic elements without oligonucleotide handles. These hybrid supramolecular-DNA structures allow for advanced levels of control over 1D dynamic platforms with responsive regulatory elements at the interface with biological systems

Generation of gas-phase ions from charged clusters: an important ionization step causing suppression of matrix and analyte ions in matrix-assisted laser desorption/ionization mass spectrometry

RATIONALE: Ionization in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a very complicated process. It has been reported that quaternary ammonium salts show extremely strong matrix and analyte suppression effects which cannot satisfactorily be explained by charge transfer reactions. Further investigation of the reasons causing these effects can be useful to improve our understanding of the MALDI process. METHODS: The dried-droplet and modified thin-layer methods were used as sample preparation methods. In the dried-droplet method, analytes were co-crystallized with matrix, whereas in the modified thin-layer method analytes were deposited on the surface of matrix crystals. Model compounds, tetrabutylammonium iodide ([N(Bu)4 ]I), cesium iodide (CsI), trihexylamine (THA) and polyethylene glycol 600 (PEG 600), were selected as the test analytes given their ability to generate exclusively pre-formed ions, protonated ions and metal ion adducts respectively in MALDI. RESULTS: The strong matrix suppression effect (MSE) observed using the dried-droplet method might disappear using the modified thin-layer method, which suggests that the incorporation of analytes in matrix crystals contributes to the MSE. By depositing analytes on the matrix surface instead of incorporating in the matrix crystals, the competition for evaporation/ionization from charged matrix/analyte clusters could be weakened resulting in reduced MSE. Further supporting evidence for this inference was found by studying the analyte suppression effect using the same two sample deposition methods. CONCLUSIONS: By comparing differences between the mass spectra obtained via the two sample preparation methods, we present evidence suggesting that the generation of gas-phase ions from charged matrix/analyte clusters may induce significant suppression of matrix and analyte ions. The results suggest that the generation of gas-phase ions from charged matrix/analyte clusters is an important ionization step in MALDI-MS. Copyright © 2016 John Wiley & Sons, Ltd

Supramolecular chemistry in biodevices

Supramolecular chemistry offers diverse opportunities for fabrication and improvement of biodevices. Applications in this field can be pursued both on surfaces and in solution, for example via the functionalization of biomolecules (peptides, proteins, DNA, etc) with supramolecular tags for selective and reversible binding, immobilization and orientation. The targeted fields of application range from diagnostics for the detection and quantification of biomarkers to biomaterials that mediate controlled interactions with eukaryotic cells or bacteria, hence, promoting their subsequent development towards biosensors or implants. Thus, supramolecular concepts like host-guest interactions offer dynamic platforms and a high versatility and will be the focus of this review. Such supramolecular cyclic host molecules create great opportunities for drug delivery, while the dynamicity and reversibility of these assemblies open the door to acquire self-healing materials