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.
High‐density peptide arrays with solid amino acid particles: Intermittent “freezing” of activated amino acid derivatives within solid particles allows a laser printer or a chip to spatially address these “postal packages”. Subsequent parallel coupling is started simply by melting a whole layer of 20 different amino acid particles, freeing the hitherto immobilized amino acids and resulting in the coupling of all 20 different amino acids to the support in a single coupling step.
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.
Cyclase‐free at last : A methylene‐interrupted meso‐bis‐epoxide was stereoselectively converted into dihydroxy‐tetrahydrofuran derivatives with excellent de and ee values through an enzyme‐triggered nucleophilic hydrolysis/cyclisation cascade. Molecular modelling showed that the point of enzyme attack was determined by the stereospecificity of the epoxide hydrolase, whereas the stereochemical course of the cyclisation step was solely governed by Baldwin's rules and did not invoke the involvement of a “cyclase”.
Where a noncovalent interaction is better than a covalent bond : The most stabilising cross‐strand pairs were incorporated into an irregular β‐hairpin, loop 3 of vammin. 1H and 13C NMR conformational analyses of these designed peptides indicated that an edge‐to‐face Trp???Trp interaction leads to a β‐hairpin that is more stable than a disulfide bond.
Synthetic cancer vaccines : A number of fully synthetic vaccine candidates have been designed, chemically synthesized, and immunologically evaluated to establish a strategy to overcome the poor immunogenicity of tumor‐associated carbohydrates and glycopeptides and to determine the importance of Toll‐like receptor (TLR) engagement for antigenic responses against these compounds.
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.
New and improved : The incorporation of a 6‐chlorotryptophan (6‐Cl‐Trp) into a β‐peptide (M)‐314 helix leads to a high‐affinity hDM2 inhibitor, as demonstrated by fluorescence fluctuation analysis at single molecule resolution. When conjugated to penetratin, the newly derived hDM2 binder specifically inhibits tumour cell growth in vitro.
The conformations of all stereoisomers of PMRI cyclotetrapeptide mimetics 1 – 8 are essentially determined by the predisposition of the diamine to stabilize β‐turns. The peptide mimetics can be regarded as 3D scaffolds for designing molecules with a predictable display of the pharmacophores. We used the models for testing novel RGD analogues as αvβ3‐integrin receptor antagonists.
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.
Copper‐induced structural rearrangements of Aβ40 structure and its redox properties are described in this study. Electrochemical and fluorescent methods are used to characterise the behaviour of Aβ–Cu species. The data suggest that time‐dependent folding of Aβ–Cu species may cause changes in the redox potentials.
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.
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.
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.
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.
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.
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.
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.
Making the microbes work for us : An acyl‐carrier‐protein‐centered strategy that involves two distinct acyl‐transfer steps for generation and regiospecific attachment of the 5‐chloro‐6‐methyl‐O‐methylsalicyl group onto the C3′ position of D ‐olivose was elucidated in the biosynthetic pathway of chlorothricin. Identification of the mutant of the acyltransferase‐associated intermediate validated the critical role of the highly conserved Cys residue, which channels the acyl transfer by using its thiolate side chain as a nucleophile in a two‐step process.
