Playing polo : Small‐molecule inhibitors of polo‐like kinase 1 are mostly ATP‐competitive, and thus face enormous specificity hurdles. This communication explores the concept of inhibiting Plk1 with a small‐molecule inhibitor of the protein–protein interactions required for Plk1 function.
Interactions between C34 and N36 : Synthetic peptides with D ‐amino acid substitutions that mimic the human immunodeficiency virus (HIV) gp41 HR2 region may lead to new peptidic anti‐HIV‐1 drugs that retain potent antiviral activity while being more resistant to proteolytic degradation.
Targeting Bcl‐x L /Bak : A family of rationally designed α‐helix mimetics with improved solubility and synthetic feasibility based on a benzoylurea scaffold is presented. These benzoylurea derivatives favor a linear conformation stabilized by an intramolecular hydrogen bond, and are able to mimic the spatial projection of the i, i+4, and i+7 residues of an α‐helix. Binding affinities of the benzoylurea derivatives to Bcl‐xL have been assessed using fluorescence polarization competition assays and isothermal titration calorimetry.
C/Si switch : Twofold sila‐substitution (C/Si exchange) in the RXR‐selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila‐SR11237) and 5 b , respectively. Chemistry and biology of the C/Si pairs are reported.
Treating African trypanosomiasis : The synthesis and biological evaluation of novel 1‐alkyloxy and 1‐benzyloxyadamantano 2‐guanylhydrazones, their 1‐dioxa congeners and two 1‐benzyladamantano 2‐guanylhydrazones is reported. Preliminary structure–activity relationship data were elucidated and lead compounds suitable for further optimization were discovered.
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.
Probing the dynamin binding site : Bis‐tyrphostin ( 1 , Bis‐T), is a potent inhibitor of the phospholipid‐stimulated GTPase activity of dynamin I. Analogues of Bis‐T have significant potential as a biological probes for the dissection of endocytic pathways. Bis‐T‐derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues ( 23 and 24 ) represent the first asymmetrically substituted Bis‐T analogues to retain dynamin inhibition.
It's raining, it's porin : Fragment ligation of OmpF ion channels was achieved by using the split Psp‐GBD Pol intein; this allowed reconstitution of active trimeric porin. In combination with cysteine modification at an internal position, the porin's conductance properties were altered.
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.
A QSAR model for the prediction of CNS activity was developed and validated based on data from an in‐house database of “drug‐like” compounds. The model has demonstrated its applicability for novel chemical structures and its usefulness for the design of CNS‐focused compound libraries.
Come together right now with L ‐DOPA : Chemical cross‐linking is widely used to study protein–protein interactions. However, many cross‐linking agents suffer from low reactivity or selectivity. An efficient and selective reaction of site‐specific protein cross‐linking was achieved using genetically incorporated 3,4‐dihydroxy‐L ‐phenylalanine.
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.
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.
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.
Broad‐spectrum antibiotics with heterocyclic side chains strongly inhibit peroxidase‐catalyzed iodination in the presence of metallo‐β‐lactamase. This suggests that antibiotic resistance due to hydrolysis of the β‐lactam ring in antibiotics would have negative effects on thyroid activity.
Docking‐based virtual screening : Flexible docking, scoring, and virtual screening of ligand databases are on the way to fulfilling the promise. Docking‐based virtual screening that targets taxane and colchicine binding sites will certainly provide new antitubulin agents.
On and off in a flash : We describe a novel, ultrafast, reversible, interstrand RNA photocrosslinking reaction via 3‐cyanovinylcarbazole nucleoside. The interstrand RNA‐photocrosslinking reaction showed a high degree of sequence specificity and can be used in the selection of a target RNA sequence.
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.
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.
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.
