Last at last : The terminal step of the gilvocarcin V (GV) biosynthetic pathway is an unusual lactone formation. Here we show that the enzyme, GilR, dehydrogenates the hemiacetal moiety of pregilvocarcin V to the lactone found in GV by using covalently bound FAD.
The 2‐aryloxazole and 2‐arylthiazole scaffolds were used for generating compounds that we characterized for their inhibitory activity toward ATP binding cassette transporters involved in multi‐drug resistance, such as BCRP and MRP1, by using tumor cell lines overexpressing each transporter. These SAR studies are a significant step toward improving the inhibitory potency against P‐glycoprotein, BCRP, and MRP1.
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.
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.
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.
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.
Molecular requirements and determinants for efficient binding to CCR5 were interpreted by computational techniques based on comparative receptor structure modeling, advanced 3D‐QSAR, docking, and shape‐based virtual screening of commercially available entry blockers. Results of this study may be valuable for predicting new HIV entry‐blocking leads.
H 3 R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.
Reducing virulence : RhlI catalyzes the synthesis of N‐butanoyl homoserine lactone (BHL), with a minor product N‐hexanoyl homoserine lactone (HHL). By using directed evolution and a genetic screen, RhlI has been engineered for enhanced production of both BHL and HHL at a similar level.
Less is more : By starting with a high‐affinity HER2‐binding 3‐helix affibody molecule, we successfully developed 2‐helix small protein binders with 5 nM affinities by using a combination of several different strategies. Our efforts clearly suggest that 2‐helix small proteins against important tumor targets can be obtained by rational protein design and engineering.
Prodigiosin : Amido‐functionalised prodigiosin‐derived compounds were synthesised via a robust and efficient synthetic route. These compounds were then evaluated against 60 human cell lines consisting of nine diverse tumour cell types and their anticancer activities were assessed.
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 .
Tacrine–melatonin hybrids are potential multifunctional drugs for Alzheimer's disease that may simultaneously palliate intellectual deficits and protect the brain against both β‐amyloid peptide and oxidative stress. Molecular modeling studies show that they target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. They are nontoxic and may be able to penetrate the CNS, according to in vitro PAMPA‐BBB assays.
Look at what the cat(ionic motif) dragged in! We report a general strategy to increase the cell permeability of β3‐peptides. Introduction of a minimal cationic motif within the folded structure of a high‐affinity β3‐peptide ligand for hDM2 led to molecules with high 314‐helical structure, high hDM2 affinity and sufficient cell permeability to upregulate p53‐dependent genes in live mammalian cells. Minimally cationic β3‐peptides represent the critical first step towards a class of protease‐resistant peptidomimetics that might modulate intracellular biological pathways.
Monooxygenase mutants : A minimal and highly enriched CYP102A1 mutant library was constructed by combining five hydrophobic amino acids in two positions. The library was screened with four different terpene substrates. Eleven variants demonstrated either a strong shift or improved regio‐ or stereoselectivity during oxidation of at least one substrate as compared to CYP102A1 wild type.
The big screen : We have devised a high‐throughput screening method for organic peroxide‐dependent P450 reactivity by taking advantage of a previously undescribed activity of catalase, which was used as reporter enzyme. This two‐step assay, followed by liquid chromatography/mass spectrometry analyses, allowed the facile identification of several new substrates for bacterial P450 enzymes.
Catch a tiger by the tail : We have demonstrated that by feeding nonmotile mutant C. jejuni bacteria with a neutral azide‐labelled pseudaminic acid precursor we can restore their ability to generate functional flagella. The presence of azido‐pseudaminic acid on the surface of the flagella provides a bio‐orthogonal chemical handle that can be used to modify the flagellar proteins.
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.
Out of the green! Precursor‐directed biosynthesis allowed for the production of new nostocarboline derivatives that display phytotoxic and algicidal properties—in a phototrophic organism. The mechanism of action includes downregulation of photosynthesis, as demonstrated by chlorophyll‐a fluorescence imaging.
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.
