Thymine Photodimers. Two-dimensional NMR and photo-CIDNP studies

De erfelijke eigenschappen van levende organismen zijn vastgelegd in DNA molekulen in de vorm van een specifieke volgorde van de basen adenine, cytosine, guanine en thymine. Het essentieel voor de ontwikkeling van levende organisemen, dat de DNA molekulen zeer vaak gedupliceerd kunnen worden zoder dat de vastgelegde code noemenswaardig veranderd. Dit vereist een extreem hoge stabiliteit van het DNA molekuul. In schijnbare tegenspraak hiermee is het feit, dat het DNA wordt blootgesteld aan een groot aantal externe factoren, die de genetische code kunnen verminken. Een van die factoren is het ultraviolet licht. De belangrijkste schade veroorzaakt door ultraviolet licht is het thymine dimeer, dat op twee manieren kan worden gevormd. ... Zie: Samenvattin

Synthesis of a tricyclic hexapeptide –via two consecutive ruthenium-catalyzed macrocyclization steps– with a constrained topology to mimic vancomycin's binding properties toward D-Ala-D-Ala dipeptide

A ring-closing metathesis (RCM) - peptide coupling - ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) strategy was developed to synthesize a tricyclic hexapeptide in which the side chain to side chain connectivity pattern resulted in a mimic with a topology that effectively mimics the bioactivity of vancomycin as a potent binder of the bacterial cell wall D-Ala-D-Ala dipeptide sequence and more importantly being an effective inhibitor of bacterial growth

A new perspective on fungal metabolites:Identification of bioactive compounds from fungi using zebrafish embryogenesis as read-out

There is a constant need for new therapeutic compounds. Fungi have proven to be an excellent, but underexplored source for biologically active compounds with therapeutic potential. Here, we combine mycology, embryology and chemistry by testing secondary metabolites from more than 10,000 species of fungi for biological activity using developing zebrafish (Danio rerio) embryos. Zebrafish development is an excellent model for high-throughput screening. Development is rapid, multiple cell types are assessed simultaneously and embryos are available in high numbers. We found that 1,526 fungal strains produced secondary metabolites with biological activity in the zebrafish bioassay. The active compounds from 39 selected fungi were purified by liquid-liquid extraction and preparative HPLC. 34 compounds were identified by a combination of chemical analyses, including LCMS, UV-Vis spectroscopy/ spectrophotometry, high resolution mass spectrometry and NMR. Our results demonstrate that fungi express a wide variety of biologically active compounds, consisting of both known therapeutic compounds as well as relatively unexplored compounds. Understanding their biological activity in zebrafish may provide insight into underlying biological processes as well as mode of action. Together, this information may provide the first step towards lead compound development for therapeutic drug development

A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Mechanistic insights into the C₅₅-P targeting lipopeptide antibiotics revealed by structure-activity studies and high-resolution crystal structures

The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C(55)-P). In this study we describe the design and synthesis of new C(55)-P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C(55)-P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C(55)-P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin

Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy

A new efficient post-assembly strategy for the synthesis of sulfated peptides

No abstract available