Protein Mimicry: A New Dimension for Peptides as Lead Compounds?

A short peptide as mimic for the hemopoietic growth factor erythropoietin (containing 165 amino acids) could be identified with the aid of peptide libraries on phage surfaces (phage display). The crystal structure of a peptide dimer complexed with two erythropoietin receptors (shown on the right) provides an insight into the molecular basis of this protein mimicry.     

Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein–Protein Interactions

Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein–protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.     

Engineering a flexible and mechanically strong composite electrolyte for solid-state lithium batteries

Lithium-ion batteries(LIBs)have greatly facilitated our daily lives since 1990s[1,2].To meet the ever-increasing demand on energy density,Li metal is seen as the ultimate anode because of its ultra-high specific capacity(3860 m Ah/g)and the lowest electrochemical potential(-3.04 V vs.the standard hydrogen electrode)[3–6].However,issues of Li metal anode,such as Li dendrite formation and large volume change during plating/stripping。     

How Does a Membrane Protein Achieve a Vectorial Proton Transfer Via Water Molecules?

We present a detailed mechanism for the proton transfer from a protein‐bound protonated water cluster to the bulk water directed by protein side chains in the membrane protein bacteriorhodopsin. We use a combined approach of time‐resolved Fourier transform infrared spectroscopy, molecular dynamics simulations, and X‐ray structure analysis to elucidate the functional role of a hydrogen bond between Ser193 and Glu204. These two residues seal the internal protonated water cluster from the bulk water and the protein surface. During the photocycle of bacteriorhodopsin, a transient protonation of Glu204 leads to a breaking of this hydrogen bond. This breaking opens the gate to the extracellular bulk water, leading to a subsequent proton release from the protonated water cluster. We show in detail how the protein achieves vectorial proton transfer via protonated water clusters in contrast to random proton transfer in liquid water.     

Native Top-Down Mass Spectrometry and Ion Mobility MS for Characterizing the Cobalt and Manganese Metal Binding of α-Synuclein Protein

Structural characterization of intrinsically disordered proteins (IDPs) has been a major challenge in the field of protein science due to limited capabilities to obtain full-length high-resolution structures. Native ESI-MS with top-down MS was utilized to obtain structural features of protein-ligand binding for the Parkinson’s disease-related protein, α-synuclein (αSyn), which is natively unstructured. Binding of heavy metals has been implicated in the accelerated formation of αSyn aggregation. Using high-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry, native top-down MS with various fragmentation methods, including electron capture dissociation (ECD), collisional activated dissociation (CAD), and multistage tandem MS (MS³), deduced the binding sites of cobalt and manganese to the C-terminal region of the protein. Ion mobility MS (IM-MS) revealed a collapse toward compacted states of αSyn upon metal binding. The combination of native top-down MS and IM-MS provides structural information of protein-ligand interactions for intrinsically disordered proteins.

Open image in new window

Graphical Abstract ?

     

DNA microarrays: is there a role for analytical chemistry?

DNA microarrays, or "DNA chips", represent a relatively new technology that is having a profound impact on biology and medicine, yet analytical research into this area is somewhat sparse. This article presents an overview of DNA microarrays and their application to gene expression analysis from the perspective of analytical chemistry, treating aspects of array platforms, measurement, image analysis, experimental design, normalization, and data analysis. Typical approaches are described and unresolved issues are discussed, with a view to identifying some of the contributions that might be made by analytical chemists.     

Flavonoids: A Myth or a Reality for Cancer Therapy?

Nutraceuticals are biologically active molecules present in foods; they can have beneficial effects on health, but they are not available in large enough quantities to perform this function. Plant metabolites, such as polyphenols, are widely diffused in the plant kingdom, where they play fundamental roles in plant development and interactions with the environment. Among these, flavonoids are of particular interest as they have significant effects on human health. In vitro and/or in vivo studies described flavonoids as essential nutrients for preventing several diseases. They display broad and promising bioactivities to fight cancer, inflammation, bacterial infections, as well as to reduce the severity of neurodegenerative and cardiovascular diseases or diabetes. Therefore, it is not surprising that interest in flavonoids has sharply increased in recent years. More than 23,000 scientific publications on flavonoids have described the potential anticancer activity of these natural molecules in the last decade. Studies, in vitro and in vivo, show that flavonoids exhibit anticancer properties, and many epidemiological studies confirm that dietary intake of flavonoids leads to a reduced risk of cancer. This review provides a glimpse of the mechanisms of action of flavonoids on cancer cells.     

Ersatzteillager Mensch? Tissue Engineering

The increased expectation of life of the people in the developed nations has enhanced the needs for permanent or temporal substitutions of deseased, injured, or aged organs and tissues. This is one of the great challenges the medicine presently faces. The regenerative medicine comprises developments and applications in the fields of implants, cell‐based therapies and tissue engineering.     

In Vitro Selection of a DNA Aptamer Targeting Degraded Protein Fragments for Biosensing

Protein biomarkers often exist as degradation fragments in biological samples, and affinity agents derived using a purified protein may not recognize them, limiting their value for clinical diagnosis. Herein, we present a method to overcome this issue, by selecting aptamers against a degraded form of the toxin B protein, which is a marker for diagnosing toxigenic Clostridium difficile infections. This approach has led to isolation of a DNA aptamer that recognizes degraded toxin B, fresh toxin B, and toxin B spiked into human stool samples. DNA aptamers selected using intact recombinant toxin B failed to recognize degraded toxin B, which is the form present in stored stool samples. Using this new aptamer, we produced a simple paper-based analytical device for colorimetric detection of toxin B in stool samples, or in the NAP1 strain of Clostridium difficile. The combined aptamer-selection and paper-sensing strategy can expand the practical utility of DNA aptamers in clinical diagnosis.     

Infinite square well with a sinusoidal bottom: a candidate for the Klauder phenomenon?

In contrast to a recent observation, we notice that a particle in a box with any cosine bottom does not show up the Klauder phenomenon when the perturbation is gradually reduced to zero. Both perturbative and variational approaches have been pursued. The case of a harmonic oscillator perturbed by a similar potential is additionally studied. No peculiarity is observed anywhere in this case too. Possible reasons behind the phenomenon are sought to rationalize our findings.     

Preparation of CI‐1027 Glucuronide: Metabolite of a Remarkable Lipid‐Modulating Agent

Abstract

The preparation of the 1β‐glucuronide of the diacid, CI‐1027, is described. The key synthetic steps are coupling of the mono‐protected acid with bromoglucuronide, deacetylation, and enzymatic hydrolysis.     

Terahertz spectroscopy: a powerful new tool for the chemical sciences?

Terahertz spectroscopy is only now beginning to make its transition from initial development by physicists and engineers to broader use by chemists, materials scientists and biologists, thanks to the increasing availability of commercial terahertz spectrometers. With the unique insights that terahertz spectroscopy can provide into intermolecular bonding and crystalline matter, it could prove to be an invaluable addition to the chemist's analytical toolset. This tutorial review aims to give an introduction to terahertz spectroscopy, its techniques, equipment, current applications and potential for the chemical sciences to a broad readership.     

Engineering of a bis-chelator motif into a protein α-helix for rigid lanthanide binding and paramagnetic NMR spectroscopy

Attachment of two nitrilotriacetic acid-based ligands to a protein α-helix in an i, i + 4 configuration produces an octadentate chelating motif that is able to bind paramagnetic lanthanide ions rigidly and with high affinity, leading to large pseudocontact shifts and residual dipolar couplings in the NMR spectrum.