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.
Illuminating an ER enzyme : We report on the design and synthesis of a fluorogenic chemical sensor ( 1 ) to measure sphingosine‐1‐phosphate lyase activity in high‐throughput screening formats, as well as its validation using lyase knockout (Sgpl1?/?) cells.
Stretch out : An elastic light‐scattering‐based method that makes use of phantom nanoparticles as a substrate organizer (see illustration) allowed the quantitative evaluation of the molecular recognition events between a series of inactivated mutants of phospholipase D and lysophosphatidylcholine. The results highlight the remarkable effects on binding capability caused by single amino acid substitutions.
PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs particularly useful for treatment of a wide variety of immune and inflammatory disorders. Structural optimization of thioxoquinazoline derivatives led to new compounds with very interesting profiles as PDE7 or PDE7/PDE4 dual inhibitors, which may be further developed as new drugs for inflammatory and neurological diseases.
Decorating pradimicin : Three tailoring enzymes in the pradimicin biosynthetic pathway have been investigated. PdmN and PdmJ were identified as a D ‐amino acid ligase and a C‐5 P450 hydroxylase, respectively, whereas PdmW was deduced to be the C‐6 P450 hydroxylase.
A panel of new potential Ras ligands was generated by decorating a tricyclic levoglucosenone‐derived scaffold with aromatic moieties. Some members of the panel show in vitro inhibitory activity toward the nucleotide exchange process on Ras and are toxic to some human cancer cell lines.
Insider information : Selective labeling of endogenous proteins within cells has been an elusive goal. Here carrier protein labeling has been optimized for visualization, isolation, and protein sequencing.
Antimycotic agents : Diverse classes of antimycotic drugs have been developed over the past decades with the goal of improving selectivity and efficacy. This review discusses both conventional and novel targets for antifungal agents and the possibility of vaccination in the treatment of invasive fungal infections.
An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago‐potentiator ADX‐47273. This effort identified key substituents in the 3‐position of oxadiazole that engendered either mGluR5 ago‐potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9‐fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.
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.
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.
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.
Roll with it : The quantitative analysis of specific miRNAs from biological samples is very likely to revolutionize diagnostics of human disease. A novel method for miRNA analysis employing rolling‐circle amplification (RCA) can homogeneously detect miRNA, even at concentrations as low as 10 fM . The use of T4 RNA ligase 2 (T4 RnL2) at elevated temperatures enables very good discrimination of miRNAs differing by a single nucleotide.
Sensing the signal : A gas chromatography–mass spectrometry (GC–MS) method for the analysis of the quorum‐sensing autoinducer‐2 is described. It allows, for the first time, the direct analysis and accurate determination of this highly water soluble signaling compound, which exists in complex equilibria. The application on the caries‐causing bacterium Streptococcus mutans is described.
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.
Cells in the balance : Programmed cell death is an important and stringently controlled process. Aberrancies in its control mechanisms can lead to disease; overactive apoptosis can cause neurodegenerative disorders, whereas deficient apoptotic activity can lead to cancer. Therefore, controlling apoptotic pathways with peptides is showing increasing promise as a strategy in drug development.
Sugar‐coated chips : Glycoside clusters are valuable tools for carbohydrate–lectin recognition studies. However, the spatial arrangement of the sugar residues is a key issue in the design of high‐affinity glycoclusters. Here the affinities of linear and antenna‐ and calixarene‐based galactoside clusters towards two lectins derived from Pseudomonas aeruginosa and Ricinus communis were compared by means of glycoarrays.
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.
Combinatorial biosynthesis meets combinatorial pharmacology, cyanobacterial style : A new antimitotic natural product with features of both dolastatins 10 and 15 was isolated from the same Floridian Symploca sp. sample that produced the histone deacetylase inhibitor largazole. Both agents in combination are more effective in inhibiting cancer cell proliferation than either agent alone.
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.
