SDS‐concentration‐dependent α‐synuclein structure : Upon interaction with SDS, αSyn folds into a structure with two antiparallel α‐helices. We show from single‐molecule FRET that αSynn adopts this conformation in an all‐or‐none fashion below the SDS critical micelle concentration. Population of the folded species is directly coupled to an increase in α‐helix content; this suggests that the entire N terminus is involved in the transaction.
Selective MMP inhibitors : Eleven α‐sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP‐2, ‐8, ‐13, and ‐14, with an interesting selectivity profile versus MMP‐9.
6‐Amino‐6‐deoxy‐5,6‐di‐ N ‐( N ′‐octyliminomethylidene)nojirimycin , a reducing analogue of N‐nonyl‐1‐deoxynojirimycin, proved to be a potent and very selective inhibitor of β‐glucosidases, including human acid β‐glucosidase. Structural studies of the enzyme–inhibitor complex showed a binding mode in which the anomeric hydroxy group is accommodated in the “wrong” α configuration.
Discovering RNA–protein interactions : A library of photoMet‐containing peptides was synthesized by using an Arg‐ and Leu‐rich α‐helical amphiphilic peptide. Irradiation of mixtures of these peptides and Rev‐responsive element (RRE) hairpin RNA promoted formation of covalent adducts. Analysis of one adduct showed that U26 in the bulged stem is responsible for covalent bond formation with the carbene intermediate. This strategy can provide important structural information about RNA–peptide interactions.
Probing the sheet : The network of hydrogen bonds formed in the outer β sheet of the nicotinic acetylcholine receptor (nAChR; see figure) is fairly robust and tolerates single amide‐to‐ester mutations throughout. However, eliminating two proximal hydrogen bonds completely destroys receptor function; this adds further support to gating models that ascribe important roles to these β strands of the nAChR extracellular domain.
Turn Bak : We present rationally designed scaffolds that mimic the spatial projection of the i, i+4, i+7, and i+11 residues of an α‐helix. A library of biphenyl derivatives was shown by competition fluorescence polarization and ITC to mimic Bak and disrupt the Bak/Bcl‐xL protein–protein interaction. 15N HSQC experiments confirmed that the surface of Bcl‐xL normally occupied by Bak was the target area of our new synthetic inhibitors.
Sweet medicine : Multimeric glycoconjugates with valencies ranging from one to four were synthesized by click chemistry. Unprecedented adhesion inhibitions of piliated E. coli to human bladder cells were recorded with the multimers; a tetravalent derivative showed inhibitory concentrations 6000‐ and 64‐fold lower than mannose and heptyl α‐D ‐mannoside, respectively.
Caught in a trap . In this study trapped polyketide species (see figure) were off‐loaded from a type III PKS by novel nonhydrolyzable malonyl coenzyme A analogues in which a methylene group or an oxygen atom replaces the sulfur atom of malonyl‐CoA. This strategy allows the straightforward characterisation of intermediates of polyketide biosynthesis by LC‐HR‐ESI‐MS/MS and provides valuable insights on the mechanism and timing of polyketide formation.
Spicing it up with fluorine : Enantiomers of α‐fluorinated capsaicin 2 , have been prepared by organocatalytic electrophilic fluorination and have been used as probes for the binding conformation of capsaicin to the TRPV1 pain receptor. No enantiomeric bias is observed, thus suggesting an extended binding conformation along the molecular axis.
Light up galectin: Photoprobes based on thiodigalactoside were prepared for galectin‐3, a lectin linked to cancer. The probes contained either benzophenone or acetophenone moieties as the photolabel for covalent attachment to the protein. One particular probe labeled galectin‐3 selectively, even in the presence of cell lysate.
Enzyme‐mediated synthesis of phosphatidylinositol : Engineered phospholipase D enzymes enable the synthesis of phosphatidylinositol by transphosphatidylation. The 1‐ or 3‐hydroxy group of myo‐inositol is selectively reacted.
Artificial synapses for femtomolar detection : Amperometry at platinized carbon fibre electrodes has been used to unravel the complexity of β‐lapachone's effects on cellular oxidative stress. α‐Lapachone, the pharmacologically inactive para‐quinone isomer, did not display such characteristics, but over longer incubation periods both quinones induced apoptosis. The observed effects were interpreted in terms of two mechanisms involving opposite reactivities of quinones in living cells.
Novel and potent inhibitors of Plasmodium falciparum plasmepsin II were identified by post‐processing the results of a docking screening with BEAR, a recently reported procedure for the refinement and rescoring of docked ligands in virtual screening. FRET substrate degradation assays performed on the 30 most promising compounds resulted in 26 inhibitors with IC50 values ranging from 4.3 nM to 1.8 μM .
Virtual screening discovered two prospective hits as potential leads for aldose reductase inhibition. Based on their crystal structures with the enzyme, a systematic optimization has been performed to reveal a first structure–activity relationship. A central thiophen moiety and a terminal nitro group exhibit the best binding properties.
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.
A selective 5‐HT 1A receptor agonist : A new series of ligands acting at 5‐HT1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5‐HT1A/α1D>150), and represents a new 5‐HT1A agonist chemotype.
The spatiotemporal expression of cannabinoid receptors and endocannabinoid‐metabolising enzymes during brain development guides major developmental processes including neurogenesis, cell differentiation, cell migration, neuronal specification and synaptogenesis.
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.
Combating glycolipid storage disorders : LABNAc was prepared in an efficient 11‐step procedure from D ‐lyxonolactone. The enantiomer DABNAc was also prepared from L ‐lyxonolactone. Preliminary cellular studies indicate that these compounds may find utility as chemical chaperones for the treatment of Tay‐Sachs and Sandhoff diseases.
Dynamic and rigid : The prion HET‐s(218–289) consists, in its amyloid form as shown here, of highly ordered and rigid parts and a very dynamic loop, which could be of great importance for fibril formation. Indeed, MD simulations explain the experimental NMR results and describe the dynamics of the salt‐bridge network that stabilizes the amyloid fibril, a feature not easily accessible by experiment.
