ChemBioChem最新文献

This paper focused on the DNA-binding properties of novel dicationic cyanine dyes, in which pyridinium centers are linked by bridges of different functionalities. We found that dye 1, bearing a flexible butyl-4-methylpyridinium terminal fragment, has the ability to bind to the DNA groove. The attachment of a quite rigid para-xylylene-4-methylpyridinium unit as a terminal group in dye 2 contributed to dual DNA-binding modes: intercalation and groove binding. We tested the encapsulation ability and the effect on the dye-DNA binding mode by using a synthetic molecular container such as CB[7]. Unexpectedly, monitoring dye-DNA interaction in the presence of CB[7] revealed that dye molecules partially remain in DNA frameworks, even though they had a higher affinity towards CB[7]. In the case of dye 1, the transformation of dimeric forms to the left-handed aggregates to yield a ternary system CB[7]-dye-DNA occurred. For dye 2, reversibility of intercalation and a slight right-handed aggregation templated by DNA are observed. A cytotoxicity and ability of dyes to stain the living cells in their free and encapsulated forms have been investigated. These findings provide useful information about ligand-DNA interactions, which are valuable for the rational design of drug delivery systems and platforms for cellular imaging and therapy.

Hypoxylon lienhwacheense, a fungal species with an unclear taxonomic placement within the Hypoxylaceae, presented a highly rare stromatal secondary metabolite profile. Isolation of its major stromatal constituents led to the discovery of a novel tropolone-maleidride hybrid molecule, lienhwalide A 5, in addition to the known cordyanhydride B 6, its new derivative 7, and binaphthalenetetraol 8. Unexpectedly, H. lienhwacheense produced in liquid cultures various lienhwalide A congeners 9-11. Their structures and relative configurations were elucidated using HRMS and NMR spectroscopy, with their absolute configurations determined using X-ray analysis of a semisynthetic brominated derivative of 9 and synthesising MTPA-esters of 11. Feeding experiments with 13C-labelled precursors (13C-methionine, 1-13C- and U-13C6-glucose) revealed insights into the biogenesis of tropolone and maleidride moieties, according to 13C couplings and INADEQUATE NMR data. Genome analysis identified two separate BGCs responsible for these moieties, and heterologous expression experiments provided further insights into the interplay of both clusters during the biosynthesis of these hybrid natural products. Remarkably, lienhwalides exhibited reduced toxicity and enhanced antibacterial selectivity compared to related fungal tropolones.

The aspartase/fumarase superfamily is a group of homologous enzymes that promote the reversible elimination of functional groups from succinyl-containing compounds, typically yielding fumarate as the common product. Over the past 50 years, members of this superfamily have continuously demonstrated their power and significance as biocatalysts. This is exemplified by ethylenediamine-N,N-disuccinic acid (EDDS) lyase, which was shown to have an extraordinary amine scope, enabling the production of a wide variety of N-substituted aspartic acids. In this work, we used this enzyme as a starting point for a homology-based strategy to expand the biocatalytic toolbox of C-N bond-forming enzymes. We selected 13 enzymes for biochemical characterization, and identified several EDDS-lyase homologues that can accept L-amino acids as substrates in the hydroamination of fumarate to produce the corresponding aminopolycarboxylic acids. Lastly, we carried out a sequence similarity network analysis of the aspartase/fumarase superfamily, which suggests that EDDS lyase and its homologues may represent a distinct isofunctional subfamily, laying the foundations for future enzyme discovery and engineering campaigns.

Protein-based probes constructed via genetically encoding acetyl lysine (AcK) or its close analogs represent an important way to detect protein lysine deacetylases. Existing reported probes exhibit excellent sensitivity to NAD+-dependent sirtuins but lack responsiveness to Zn2+-dependent histone deacetylases (HDACs). Herein, we reformed the probe design by replacing the genetically encoded AcK with trifluoroacetyl lysine (TfAcK) and generated fluorescent and bioluminescent probes that could respond specifically to HDAC8 recombinantly expressed in E. coli and to endogenous HDACs in mammalian cells. We believe these probes would benefit the biological investigation of HDAC8 and promisingly some other HDACs, as well as the discovery of innovative HDAC inhibitors.

Actinorhodin (ACT) from Streptomyces coelicolor A3(2) is an aromatic polyketide antibiotic with a benzoisochromanequinone (BIQ) skeleton. Although actVI-ORF3 and actVI-ORF4 are not essential for ACT biosynthesis, homologous genes to these are present in the biosynthetic gene clusters of BIQ lactones. In this study, ActVI-ORF3 was identified as a cofactor-independent enzyme with lactonization activity, using ACT as a substrate. ActVI-ORF3 recognized dihydrokalafungin and 8-hydroxykalafafungin, which share the same pyran-ring configuration as ACT, but not nanaomycin A, which has an opposite configuration. In contrast, ActVI-ORF4 functioned as an NAD(P)-dependent oxidoreductase, catalyzing the delactonization of BIQ lactones. Conversion experiments using isotopically labeled compounds revealed that both lactonization and delactonization reactions of these enzymes yielded products in which the carboxyl oxygen at the C1 position was retained. Subsequently, we reexamined the accumulation of ACT-related compounds in the actVI-ORF3 and actVI-ORF-4 disruptants. The results suggested that ACT intermediates are predominantly pooled in the bacteria as (S)-DNPA rather than in lactone-form. The contribution of ActVI-ORF4 to metabolic flux is not significant, and endogenous reductases can convert these intermediates to the dihydro form, which subsequently re-enters the ACT biosynthetic pathway.

The development of broad-spectrum antiviral drugs effective against a wide variety of viruses is of significant practical importance. Derivatives of perylene, a pentacyclic aromatic hydrocarbon, demonstrate pronounced antiviral activity. These compounds primarily act as membrane-active singlet oxygen photogenerators, disrupting virions and inhibiting their fusion with a host cell membrane. Modifying the perylene core allows for chemical diversification of antiviral photosensitizers. Additionally, achieving a bathochromic shift in absorbance is crucial for effective treatment of superficial lesions, as it facilitates deeper tissue penetration of therapeutic light. In this work, donor-acceptor perylenylethylenes and (perylenethienyl)ethylenes were synthesized and evaluated for their spectral properties, singlet oxygen photogeneration and inhibition activity against vesicular stomatitis virus (VSV), a representative enveloped virus. The incorporation of a thiophene unit into the molecule significantly enhanced both the singlet oxygen generation ability and the antiviral activity. These findings provide useful insights into the relationship between the structure, spectral/photochemical properties and biological activity of perylene-based photosensitizers.

Based on the Watson-Crick base pairing principle, precisely programmable metal framework nucleic acids (mFNA) have evolved from one-dimensional to three-dimensional nanoscale structures, a technological advancement attributed to progress in DNA nanotechnology. mFNA are a new type of nanomaterial formed by using FNAs as precise templates to guide the ordered assembly and self-assembly of metal ions, metal salts (such as calcium phosphate, calcium carbonate, etc.), metal nanoclusters, metal nanoparticles, or metal oxide nanoparticles. Compared to traditional FNAs, mFNA not only inherits the powerful programmed self-assembly capabilities of nucleic acids but also incorporates the unique physicochemical properties of inorganic metal nanomaterials. This intersection of organic and inorganic chemistry presents broad application prospects in fields such as biology, chemistry, materials science, and energy science. This review, based on the principles related to FNAs, introduces the concept of mFNA for the first time, aiming to explore the fundamental connections between nanoscale FNAs and metal materials. Additionally, the article focuses on the construction methods and functional characteristics of mFNA. Finally, the current challenges faced by mFNA are reviewed, and their future development is anticipated, providing detailed information for a comprehensive understanding of the research progress in mFNA.

The histamine subtype 3 receptor (H₃R) is mainly expressed in the brain, where it plays a key role in various neurological functions. This brain imaging, featuring glowing neural connections, highlights the high expression of H₃R. The molecular structure approaching the brain represents new Positron Emission Tomography (PET) probes for precise brain imaging. The light trail indicates the potential of this PET probe to visualize H₃R, providing insights into brain function and pathology. More details can be found in Research Article 10.1002/cbic.202400655 by Magnus Schou, Steven H Liang, and co-workers.

Green algae can be engineered to make a range of functionalized sesquiterpenes like those used in the fragrance industry. Localizing P450 oxidoreductases in the algal chloroplast allows photosynthesis to increase the diversity of chemical products made from the engineered cells. Here, green algae (liquid) are shown in contact with a solvent to collect the chemicals and the fictitiously large chemicals are shown floating from the algae and the solvent with perfume bottles in the background. More details can be found in article 10.1002/cbic.202400902 by Kyle J. Lauersen and co-workers.

This cover image depicts the multifunctional and multitargeting nature of the tppz-based-dinuclear Ru(II) complexes for different biomedical applications, including as DNA probes, organelle imaging agents, and cancer photo-therapeutics. More details can be found in article 10.1002/cbic.202400931 by Rajesh Kushwaha, and Samya Banerjee.