Transforming the neuroactive toxins of cone snails into small‐size compounds poses a challenge due to the presence of multiple disulfide bridges. Herein we describe our successful efforts in minimizing the size of μ‐conotoxin while retaining its biological activity.
Point of recognition : Surface plasmon resonance was used to study the role of the viral membrane in HIV immunogen recognition by the monoclonal antibodies 2F5 and 4E10. The different behaviour of the antibodies towards membranes and immunogens embedded within membranes, provide insight into the emerging membrane‐based or membrane‐conformation strategies of immunogen design.
Stop dividing : In the quest for antitumorigenic compounds, aurora A kinase has recently emerged as a potential drug target. In this paper three novel aurora inhibitors (shown in the illustration) have been tested for their biological activity in cultured cells. One of them (TC‐28) appears to be a promising specific aurora A inhibitor in vivo.
Site‐specific immobilization of peptides and proteins is crucial to ensure their functionality in surface‐based assays. We report the use of aniline‐catalyzed oxime ligations as a very efficient and broadly applicable method to covalently attach the N terminus of proteins and peptides to a surface functionalized with alkoxy‐amine groups.
Finding the right fit : Herein, we report on the development of novel steric probes and present initial insights into their interplay with DNA polymerases. Our findings provide experimental evidence for varied enzyme–substrate interactions that might account for the varied selectivity previously observed.
Anchors aweigh! The synthesis of tryptophan–amphotericin B conjugates (see figure) is described. The membrane‐anchoring effect of tryptophane was thus combined with the pore‐formation effect of amphotericin B leading to high channel activity in sterol‐free liposomes.
One enzyme, many substrates . The substrate specificity of a lantibiotic biosynthetic enzyme, lacticin 481 synthetase, was probed by using synthetic prepeptides containing a variety of nonproteinogenic amino acids, including unnatural α‐amino acids, β‐amino acids, D ‐amino acids, and peptoids.
Access to enantiopure β‐amino acids : β‐Aminopeptidases are hydrolases that possess the unique ability to cleave N‐terminal β‐amino acids from peptides and amides. Hydrolysis of racemic β‐amino acid amides catalyzed by these enzymes displays enantioselectivity with strong preference for substrates with the L ‐configuration, and gives access to various aliphatic β‐amino acids of high enantiopurity.
Copper‐induced structural rearrangements of Aβ40 structure and its redox properties are described in this study. Electrochemical and fluorescent methods are used to characterise the behaviour of Aβ–Cu species. The data suggest that time‐dependent folding of Aβ–Cu species may cause changes in the redox potentials.
Where a noncovalent interaction is better than a covalent bond : The most stabilising cross‐strand pairs were incorporated into an irregular β‐hairpin, loop 3 of vammin. 1H and 13C NMR conformational analyses of these designed peptides indicated that an edge‐to‐face Trp???Trp interaction leads to a β‐hairpin that is more stable than a disulfide bond.
Protein compatible . Olefin metathesis has emerged as a viable strategy for site‐selective protein modification. This minireview traces its development from early peptide models and metathesis in water to its ultimate application to protein substrates. Prospects in chemistry and biology are also discussed.
Weak recognition processes : Weak calcium‐mediated carbohydrate–carbohydrate interactions have been detected by DOSY and TRNOESY NMR methods by employing a gold glyconanoparticle as a multivalent system. In addition, 3D models of trisaccharide‐CaII‐trisaccharide complexes based on results from molecular dynamics simulations are proposed.
Saghatelian and colleagues recently introduced a global metabolite‐profiling approach that allows protein–metabolite interactions (PMI) to be identified. This approach represents an excellent strategy and valuable tool for unraveling the many secrets of the metabolome. The key features of the methodology will be summarized here.
The foreign lesion : The mechanistic questions for DNA base damage detection by repair proteins are discussed in this Minireview. Repair proteins could either probe and locate a weakened base pair that results from base damage, or passively capture an extrahelical base lesion in the first step of damage searching on double‐stranded DNA. How some repair proteins, such as AGT (see figure), locate base lesions in DNA is still not fully understood.
An inference network model for molecular similarity searching: The similarity search problem is modeled using inference or evidential reasoning under uncertainty. The inference network model treats similarity searching as an evidential reasoning process in which multiple sources of evidence about compounds and reference structures are combined to estimate resemblance probabilities.
A series of arotinoids with a central benzofuran or naphthofuran ring structure were synthesized by an efficient three‐step process. Most of these 3‐substituted naphthofuran arotinoids are potent agonists of the retinoic acid receptor (RAR) subtypes, with activities in the nanomolar range.
On the scaffold : Grafting protein epitopes onto conformationally designed scaffolds represents a very promising approach to protein ligand design, with potential applications in many areas of chemical biology and molecular medicine. The highlighted article describes the design and anticancer activity of novel p53/MDM2 inhibitors built upon a scorpion toxin scaffold. Other approaches to protein epitope mimetics are also briefly discussed.
Peptides that inhibit cyclin‐dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with β‐amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X‐ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.
Highly specific protein labeling : Photogenerated quinine methides (QMs) can act as highly specific light‐controllable protein affinity labeling reagents, broadening their applications to the study of protein–ligand and protein–protein interactions. The reactions between QMs and nucleophiles are less heterogeneous than those of other photogenerated active intermediates such as carbenes and nitrenes, making it easier to identify labeled species.
The electronic and physical structure of the active centre of nitrogenase is described from an inorganic point of view, the central main‐group element is determined and its role within the cluster is explained.
