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The crystal structure of CCR2 chemokine receptor in a complex with two different antagonists—one orthosteric the other allosteric—which functionally cooperate to inhibit CCR2. Small-molecule chemokine receptor antagonists Chemokine receptors are a family of G-protein-coupled receptors that regulate the migration of immune cells; their function has been implicated in a range of diseases. Two groups reporting in this issue of Nature describe crystal structures of two different chemokine receptors bound to small-molecule inhibitors. Tracy Handel and colleagues describe the structure of CCR2—a promising drug target for autoimmune, inflammatory and metabolic diseases as well as cancer—bound to orthosteric (BMS-681) and allosteric (CCR2-RA-[ R ]) antagonists. Fiona Marshall and colleagues describe the structure of CCR9—involved in immune cell recruitment to the gut and a promising drug target in inflammatory bowel disease—in complex with the selective CCR9 antagonist vercirnon. Both CCR2 and CCR9 structures reveal an allosteric pocket on the cytoplasmic face of the receptor. This allosteric pocket appears to be highly druggable, and homologous pockets may be present on other chemokine receptors. CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1 ). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases 2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer 3 . These disease associations have motivated numerous preclinical studies and clinical trials 4 (see http://www.clinicaltrials.gov ) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts 5 , here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6 )) and allosteric (CCR2-RA-[ R ] 7 ) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[ R ] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[ R ] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

The bicyclic disulfide–containing compound thiolutin has broad antimicrobial activity and targets the essential proteasomal deubiquitinase Rpn11 and other metalloproteases, leading to inhibition of enzymatic activity through a mechanism involving zinc chelation. Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces . Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.

Tetramic acid (pyrrolidine-2,4-dione) compounds, isolated from a variety of marine and terrestrial organisms, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities. In the past decade, marine-derived microorganisms have become great repositories of novel tetramic acids. Here, we discuss the biological activities of 277 tetramic acids of eight classifications (simple 3-acyl tetramic acids, 3-oligoenoyltetramic acids, 3-decalinoyltetramic acid, 3-spirotetramic acids, macrocyclic tetramic acids, N-acylated tetramic acids, α-cyclopiazonic acid-type tetramic acids, and other tetramic acids) from marine-derived microbes, including fungi, actinobacteria, bacteria, and cyanobacteria, as reported in 195 research studies up to 2019.

A difficult synthesis is described that uses an organocopper catalyst and commercially available starting materials to give high yield and the mechanics of the reaction are elucidated through density functional theory. A difficult synthesis accomplished One of the most useful sets of reactions in organic chemistry—with applications in both research and medicinal chemistry—is the 1,4-conjugate addition of a carbanionic species to α,β-unsaturated carbonyl compounds. The corresponding 1,6-conjugate additions would be similarly useful, but it is a 'difficult' synthesis. Catalytic enantioselective 1,6-conjugate additions are uncommon, and those that incorporate moieties that can be later functionalized, such as propargyl or allyl groups, into acyclic α,β-doubly unsaturated acceptors do not exist. Here Amir Hoveyda and colleagues describe a procedure for the 1,6-conjugate addition of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. The method uses an organocopper catalyst and commercially available starting materials to give high yield, and should be extendable to other readily available unsaturated organoboron and/or organocopper systems. Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates 1 . Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown 2 . Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce 3 and are confined to reactions promoted by a phosphine–copper catalyst (with an alkyl Grignard reagent 4 , 5 , dialkylzinc or trialkylaluminium compounds 6 , 7 ), a diene–iridium catalyst (with arylboroxines) 8 , 9 , or a bisphosphine–cobalt catalyst (with monosilyl-acetylenes) 10 . 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position 11 . It is unclear why certain catalysts favour bond formation at C6, and—although there are a small number of catalytic enantioselective conjugate allyl additions 12 , 13 , 14 , 15 —related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl–boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (−)-equisetin.

The discovery of two new types of enzymes that act in tandem within the spirotetramate biosynthetic pathway to catalyze [4+2] cycloadditions offers new opportunities for mechanistic investigations of potential Diels-Alderases. The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.

Two new decalin-tetramic acid hybrid metabolites, zopfiellamides C (1) and D (2) were isolated from the marine-derived fungus Aspergillus sp. NF666. The structure determination was accomplished on the basis of HRESIMS and NMR spectral data analyses including COSY, HSQC, HMBC, and NOESY experiments. Both isolated metabolites (1 and 2) exhibited significant growth inhibition against four clinically relevant bacterial strains with minimum inhibitory concentration (MIC) values of about 12.5 μΜ. Moreover, we proposed a plausible biosynthetic pathway of zopfiellamide D (2) in this work.

Australian redback spiders Latrodectus hasseltii , known for their strong neurotoxic venom, are a quarantine threat for much of the world. Female redback spiders produce a sex pheromone that attracts males of the species, yet the compounds involved in their attraction remain unresolved. Our project set out to identify these compounds and use them to trap male redback spiders as the first step in the development of a pest management/surveillance tool for these spiders. Headspace volatiles from the silk of virgin and mated female redback spiders was collected by solid phase microextraction and analysed by gas chromatography coupled with mass spectrometry. Silk samples were also solvent extracted for analysis by liquid chromatography coupled with mass spectrometry. Comparison with synthetic standards on multiple column phases identified the candidate volatile pheromone components as 2-methylpropanoic acid, ( S )-2-methylbutanoic acid and 2-pyrrolidone, while N -3-methylbutanoyl- O -( S )-2-methylbutanoyl-L-serine was identified as the main candidate short-range cue. Bioassays with a combination of these four compounds showed similar levels of attraction to the natural virgin female’s silk. Field trapping trials using a mixture of all four compounds successfully trapped male redback spiders in New Zealand vineyards.

SF2312, a phosphonate antibiotic, directly binds and inhibits the activity of the glycolytic enzyme enolase and is selectively toxic to ENO1 -deleted glioma cells through inhibition of glycolysis and depletion of ATP. Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Cα by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora , which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase.

Fully exploiting the properties of graphene will require a method for the mass production of this remarkable material. Two main routes are possible: large-scale growth or large-scale exfoliation. Here, we demonstrate graphene dispersions with concentrations up to ∼0.01 mg ml −1 , produced by dispersion and exfoliation of graphite in organic solvents such as N-methyl-pyrrolidone. This is possible because the energy required to exfoliate graphene is balanced by the solvent–graphene interaction for solvents whose surface energies match that of graphene. We confirm the presence of individual graphene sheets by Raman spectroscopy, transmission electron microscopy and electron diffraction. Our method results in a monolayer yield of ∼1 wt%, which could potentially be improved to 7–12 wt% with further processing. The absence of defects or oxides is confirmed by X-ray photoelectron, infrared and Raman spectroscopies. We are able to produce semi-transparent conducting films and conducting composites. Solution processing of graphene opens up a range of potential large-area applications, from device and sensor fabrication to liquid-phase chemistry. Fully exploiting the properties of graphene will require a method for the mass production of this remarkable material. The dispersion and exfoliation of graphite in organic solvents can produce graphene monolayers with a yield of about 1% by weight. Moreover, these samples are free from defects and oxides, and can be used to produce semi-transparent conducting films and conducting composites.

Most of the natural products containing tetramic acid have trans configuration of the decalin moiety. Undana A ( 1 ), a new cis decalin-bearing tetramic acid metabolite was isolated from endophytic fungi Nigrospora oryzae associated with Avicennia marina . The structure was determined based on the mass and NMR spectral data together with the comparison of the literature. This is the first report of cis decalin-tetramic acid metabolite from the mangrove endophytic fungus. Compound 1 was tested for cytotoxic against L5178Y mouse cancer cells and antibacterial activity against several gram-positive including MRSA and gram-negative bacteria but was found inactive.