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.
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.
Choosing chloro : By reshaping the catalytic pocket of a catechol 1,2‐dioxygenase through a structural route alternative to evolution, novel engineered chlorocatechol dioxygenase‐like enzymes were obtained. Variants show an inversion of specificity with a preference for 4‐chlorocatechol and activity on the rarely recognised substrate 4,5‐dichlorocatechol.
Azaspiracid antibodies : Immunization of azaspiracid immunoconjugates has elicited monoclonal antibodies with distinct epitopes on the marine toxin; this will open the way toward azaspiracid diagnostics and the detection of contaminated shellfish before they can enter the food supply.
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.
The cover picture shows a “reverse” indole derivative in complex with Bacillus stearothermophilus peptide deformylase (PDF). This compound was selected from a structure–activity relationship study as a potent inhibitor of bacterial PDFs and shows antibacterial activity toward Bacillus subtilis as well as other pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. For more details, see the Full Paper by I. Artaud et al. on p. 261 ff.
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.
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.
Disarmed forces : Inhibition of the central virulence regulator ClpP by structurally refined β‐lactones resulted in dramatically reduced production of devastating virulence factors, including pyrogenic toxin superantigens derived from pathogenic multiresistant Staphylococcus aureus strains. Targeting of this virulence regulator could present an attractive strategy for neutralizing the harmful effects of bacterial pathogens, and help the host immune response to eliminate the disarmed bacteria.
SSAO/VAP‐1 substrates may be valuable for the treatment or prevention of diabetes mellitus, as they show insulin‐mimetic properties. This review highlights the importance of studying the relevant steric and electronic features in the development of new ligands with better SSAO/VAP‐1 recognition, enhanced selectivity over other amine oxidases, and improved metabolic behavior.
Into neutral : We demonstrate the unique features of a pH click peptide based on an O‐acyl isopeptide method. Under acidic conditions, the click peptide remains in a monomeric form. Upon increase of the pH to 7.4, the click peptide is quickly able to convert into Aβ1–42 through an O‐to‐N intramolecular acyl migration. Further study using this pH click peptide would elucidate the pathological role of Aβ1–42 in Alzheimer's disease.
Histamine mediates its various functions through four histamine receptor subtypes. The H3 subtype is mainly found in the central nervous system, where it modulates the release of histamine and other neurotransmitters, whereas the H4 subtype plays a crucial role in inflammatory and immunological processes. Herein, the synthesis and characterization of a conveniently accessible tritiated radioligand is reported that proved to be a versatile pharmacological probe.
Less stress : We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide‐based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA–cortical neuron model of oxidative stress.
Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α1 adrenoceptor subtypes and 5‐HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.
SAR by NMR : A series of indole compounds derived from 5‐bromo‐1H‐indole‐3‐acetohydroxamic acid were synthesized. Their inhibitory activities were evaluated against purified peptide deformylases (PDFs), and their antibacterial activities against B. subtilis, E. coli (wild type and tolC), and a variety of pathogens were also determined. The potency of the best inhibitors was related to the NMR footprints of the respective acids with 15N‐labeled E. coli Ni‐PDF.
Long‐lasting sweet proteins : The chemoenzymatic synthesis of a triazole (T)‐linked glycosylated C34 fragment from HIV‐1 gp41 is described. The glycopeptide shows high solubility, excellent fusion inhibition, and as shown in the graph, promising protease resistance.
Through construction of an iminosugar library and in situ cell‐based screening, several iminosugar compounds with the ability to stimulate IFN‐γ secretion in vitro were discovered. Among these compounds, one was able to strongly induce IFN‐γ secretion and showed remarkable antibacterial effects in vivo.
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.
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild‐type HIV‐1.
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.
