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Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared.

Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different epitopes on the same antigen, thus altering crosslinking ability. In this study, we developed BpAbs against tumor necrosis factor receptor 2 (TNFR2), which is an attractive immune checkpoint target. Using different pairs of variable regions specific to topographically distinct TNFR2 epitopes, we successfully regulated the size of BpAb-TNFR2 immunocomplexes to result in controlled agonistic activities. One particular antagonist BpAb bound TNFR2 in 1:1 ratio without unwanted signal transduction, with its structural basis revealed by cryo-electron microscopy. This antagonist suppressed the proliferation of regulatory T cells expressing TNFR2. Therefore, the BpAb format would be useful in designing specific and distinct antibody functions.

Phenyl azides substituted by an (alkylphenyl)ethynyl group facilitate benzylic sp3 (C-H) functionalization in the presence of a JohnPhosAu catalyst, resulting in indole-fused tetra- and pentacycles via divergent N- or C-cyclization. The chemoselectivity is influenced depending on the counter-anion, the electron density of the α-imino gold(I) carbene, and the alkyl groups stabilizing the benzylic carbocation originating from a 1,5-hydride shift. An isotopic labeling experiment demonstrates the involvement of an indolylgold(I) species resulting from a tautomerization that is much faster than the deauration. The formation of a benzylic sp3 (C-H) functionalization leading to an indole-fused seven-membered ring is also demonstrated.

The exploitation of nitrogen-functionalized reactive intermediates plays an important role in the synthesis of biologically relevant scaffolds in the field of pharmaceutical sciences. Those based on gold carbenes carry a strong potential for the design of highly efficient cascade processes toward the synthesis of compounds containing a fused indole core structure. This personal account gives a detailed explanation of our contribution to this sector, and embraces the reaction development of efficient gold-catalyzed cascade processes based on diversely functionalized azido-alkynes. Challenging cyclizations and their subsequent application in the synthesis of pharmaceutically relevant scaffolds and natural products conducted in an intra- or intermolecular fashion are key features of our research.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are modulated by ligands presented on MHC class I-related proteins (MR1). These cells have attracted attention as potential drug targets because of their involvement in the initial response to infection and various disorders. Herein, we have established the MR1-presentation reporter assay system employing split-luciferase, which enables the efficient exploration of MR1 ligands. Using our screening system, we identified herbal medicine-derived MR1 ligands, including coniferyl aldehyde, which have an ability to inhibit the MR1–MAIT cell axis. Coniferyl aldehyde comprises phenylpropanoids and is a novel motif for MR1 ligands. Further structure-activity relationship study revealed the key structural features of ligands required for MR1 recognition. These results will contribute to uncovering the mode of action of herbal medicines and their analogs, and to developing novel MAIT cell modulators.

Phenylazides substituted by an (alkylphenyl)ethynyl group facilitate divergent benzylic sp3(C-H) functionalization in the presence of a JohnPhosAu catalyst, via N- or C-cyclization, resulting in indole-fused tetra- and pentacycles. The chemoselectivity is influenced depending on the counter-anion (SbF6 or BARF), the electron density of the alpha-imino gold(I) carbene, and the alkyl groups stabilizing the benzylic carbocation originating from a 1,5-hydride shift. An isotop-ic labeling experiment demonstrates the involvement of an indolylgold(I) species resulting in a tautomerization that is much faster than deauration is. The formation of a benzylic sp3(C-H) functionalization resulting in an indole-fused sev-en-membered ring is also demonstrated.

Natural sphingosine analogues containing a β, β′-dihydroxy α-amino acid framework demonstrate potent antifungal or immunosuppressive activity and are potential candidates for the development of che...

Recently, various metabolites derived from host microbes have been reported to modulate the immune system, with potential involvement in health or diseases. Archaea, prokaryotic organisms, are present in the human body, but their connection with the host is largely unknown when compared with other microorganisms such as bacteria. This study focused on unique glycerolipids from symbiotic methanogenic archaea and evaluated their activities toward an innate immune receptor. The results revealed that archaeal lipids were recognized by the C-type lectin receptor Mincle and induced immune responses. A concurrent structure-activity relationship study identified key structural features of archaeal lipids required for recognition by Mincle. Subsequent gene expression profiling suggested qualitative differences between the symbiotic archaeal lipid and the pathogenic bacteria-derived lipid. These findings have broad implications for understanding the function and pathogenicity of symbiotic archaea to host health and diseases.

Biomimetic natural product synthesis is generally straightforward and efficient because of its established feasibility in nature and utility in comprehensive synthesis, and the cost-effectiveness of naturally derived starting materials. On the other hand, nonbiomimetic strategies can be an important option in natural product synthesis since (1) nonbiomimetic synthesis offers more flexibility and can demonstrate the originality of chemists, and (2) the structures of derivatives accessible by nonbiomimetic synthesis can be considerably different from those that are synthesised in nature. This review summarises nonbiomimetic total syntheses of indole alkaloids using alkyne chemistry for constructing core structures, including ergot alkaloids, monoterpene indole alkaloids (mainly corynanthe, aspidosperma, strychnos, and akuammiline), and pyrroloindole and related alkaloids. To clarify the differences between alkyne-based strategies and biosynthesis, the alkynes in nature and the biosyntheses of indole alkaloids are also outlined.

Mucosal-associated invariant T (MAIT) cells are an abundant subset of innate-like T lymphocytes. MAIT cells are activated by microbial riboflavin-derived antigens, such as 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), when presented by the major histocompatibility complex (MHC) class I-related protein (MR1). We have synthesized all stereoisomers of 5-OP-RU to investigate the effects of its stereochemistry on the MR1-dependent MAIT cell activation and MR1 upregulation. The analysis of MAIT cell activation by these 5-OP-RU isomers revealed that the stereocenters at the 2'- and 3'-OH groups in the ribityl tail are crucial for the recognition of MAIT-TCR, whereas that of 4'-OH group does not significantly affect the regulation of MAIT cell activity. Furthermore, kinetic analysis of complex formation between the ligands and MR1 suggested that 5-OP-RU forms a covalent bond to MR1 in cells within 1 hour. These findings provide guidelines for designing ligands that regulate MAIT cell functions.

A novel approach to the direct construction of tricyclic nitrogen heterocycles based on gold-catalyzed cascade cyclization of aminoallenynes is described. The expected biscyclization reaction of hydroxyisobutyryl-protected aminoallenynes was efficiently promoted by a catalytic amount of BrettPhosAuNTf₂ in the presence of iPrOH to produce 1, 2-dihydrobenzo[cd]indole derivatives in good yields. When the reaction was combined with Friedel–Crafts acylation or palladium-catalyzed N-arylation, the resulting tricyclic products were efficiently converted into nitrogen-containing polycyclic aromatic compounds (N-PACs) with highly conjugated π-electron systems. A newly obtained hexacyclic indolium salt showed characteristic concentration-dependent absorption and emission properties.

We achieved direct construction of the common pyrrolo[2, 3-d]carbazole core of aspidosperma and malagasy alkaloids by a gold-catalyzed cascade cyclization of ynamide. This reaction involves intramolecular cyclization from indole to ynamide followed by trapping of the resulting iminium intermediate. Through the use of chiral gold complexes, an enantiomerically enriched pyrrolo[2, 3-d]carbazole was obtained in up to 74% ee. This methodology was successfully applied to the asymmetric formal synthesis of vindorosine., ADDITION / CORRECTION This article has been corrected. View the notice : Correction to Construction of the Pyrrolo[2,3-d]carbazole Core of Spiroindoline Alkaloids by Gold-Catalyzed Cascade Cyclization of Ynamide -- https://doi.org/10.1021/acs.joc.0c00238

We describe the development of a strategy for the construction of the quaternary carbon stereocenter of α-tertiary amines. This strategy highlights a site-selective C–H functionalization involving an alkoxy-radical-triggered 1, 5-hydrogen transfer (1, 5-HAT) reaction of a conformationally fixed spiro-compound derived from trishydroxymethylaminomethane (Tris). The utilization of this strategy enabled an enantioselective total synthesis of myriocin, a naturally occurring sphingosine analog that displays potent immunosuppressive activity.

A gold-catalyzed reaction of phenylene-tethered allenynes with benzofurans gave 1-(naphth-1-yl)cyclopropa[b]benzofuran derivatives, whereas the reaction of 1-allenyl-2-ethynyl-3-methylbenzene derivatives in the absence of benzofurans gave acenaphthenes in good yields. These results can be rationalized by nucleophilic attack of the alkyne moiety on an activated allene to form a vinyl cation intermediate.

Neurokinin-3 receptor (NK3R) plays a pivotal role in the release of gonadotropin-releasing hormone in the hypothalamus–pituitary–gonadal (HPG) axis. To develop novel NK3R antagonists with less environmental toxicity, a series of heterocyclic scaffolds for the triazolopiperazine substructure in an NK3R antagonist fezolinetant were designed and synthesized. An isoxazolo[3, 4–c]piperidine derivative exhibited moderate NK3R antagonistic activity and favorable properties that were decomposable under environmental conditions.

Previously, we reported that intravenous injection of chondroitin sulfate (CS), followed by intravenous injection of cationic liposome/siRNA complex (cationic lipoplex) could deliver siRNA into the liver. In this study, we examined the effects of the type of cationic lipid in the liposome on siRNA delivery into the liver. We used 6 types of cationic cholesterol derivatives and 11 types of dialkyl or trialkyl cationic lipids, and prepared 17 types of cationic liposomes to evaluate the gene-silencing effect of siRNA in mouse liver following sequential injection of CS plus cationic lipoplex. In 14 types of cationic liposomes, siRNA was accumulated in the liver when cationic lipoplexes were injected immediately after CS. However, suppression of apolipoprotein B (ApoB) mRNA expression in the liver and reduction of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol level in the serum were observed only after sequential injection of CS plus ApoB siRNA lipoplex with cationic liposomes composed of N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and N,N-dimethyl-N-octadecyloctadecan-1-aminium bromide (DC-1-18)/DOPE. Based on these findings, the type of cationic lipid strongly affected the gene-silencing effect of siRNA in the liver by sequential injection of CS plus cationic lipoplex.

An efficient method for the synthesis of [1,2,4]triazolo[4,3- a]piperazine derivatives was established based on a gold(I)-catalyzed domino cyclization of an amidrazone substrate with a terminal alkyne. The amidoxime congeners were converted into [1,2,4]oxadiazolo[4,5- a]piperazine derivatives in the presence of a gold catalyst. The oxadiazolopiperazine is a promising scaffold for the design of novel inhibitors against p38 mitogen activated protein kinase (MAP kinase).

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids, zephycarinatines C and D. The key feature of the synthesis was the stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox catalysis. This cyclization enabled the construction of a 6,6-spirocyclic core structure by the addition of the carbon-centered radical onto the aromatic ring. The biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative having a keto group displayed moderate inhibitory activity against LPS-induced NO production. This approach would offer future opportunities to expand the chemical diversity derived from plicamine-type alkaloids as well as provide useful intermediates for their syntheses.

A total synthesis of polyoxamic acid has been achieved. The key feature of the synthetic route is a visible-light-mediated β-scission and carbon-to-carbon 1,5-hydrogen atom transfer (1,5-HAT) to provide the functionalized alditol under mild conditions. This type of carbon-to-carbon 1,5-HAT initiated by C(sp

The total synthesis of dictyodendrins A-F was achieved by using the gold(I)-catalyzed annulation of a conjugated diyne with N-Boc-pyrrole for direct construction of the pyrrolo[2,3-c]carbazole scaffold. Late-stage functionalization of the resulting pyrrolo[2,3-c]carbazole to introduce various substituents provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.

Heterocycle-fused indoles or indolines are distributed widely in a variety of natural products, bioactive agents, and pharmaceuticals. Herein, we describe the development of gold-catalyzed cascade reactions of anilines with diynes to form eight-membered ring-fused indoles and propellane-type indolines, both of which proceed through an intramolecular 5-endo-dig hydroamination followed by an 8-endo-dig cycloisomerization. Controllable formation of eight-membered ring-fused indoles and propellane-type indolines was achieved through selection of the ligands and/or solvents. Protic solvents such as alcohols or IPr ligand favored the formation of eight-membered ring-fused indoles, whereas the use of Buchwald’s type ligands and/or nonpolar solvents gave propellane-type indoline predominantly. This reaction provides rapid access to two types of fused nitrogen heterocycles from simple aniline derivatives.

A portable muography detector was developed for measuring infrastructure degradation and its performance was tested. The detector consists of two muon position sensitive detectors (mu-PSDs) of the area of 140 mm $\times \,\, 140$ mm, placed in a compact light-shielding box. Each mu-PSD consists of plastic scintillating fibers connected to multipixel photon counters (MPPCs). To suppress the gain deviation of the MPPCs, the box was heat insulated and its inner air temperature was maintained by Peltier cooling–heating modules. The mu-PSD pixel size was 8.75 mm $\times \,\, 8.75$ mm and the distance between the two mu-PSDs was set to 100 mm in order to achieve a solid angle resolution of 8 msr when measuring typical pieces of infrastructure at thicknesses of several tens of centimeters. The intensity of cosmic-ray muons was measured as a function of zenith angle on the ground and was found to be in good agreement with the well-known empirical formula for muon intensity at Earth’s surface. The structural interior of a seven-story concrete building was then successfully imaged with the muography detector placed in the building’s basement.

Fe(II)-coordinating hexapeptides containing three 2,2'-bipyridine moieties as side chains were designed and synthesized. A cyclic hexapeptide having three [(2,2'-bipyridin)-5-yl]-d-alanine (d-Bpa5) residues, in which d-Bpa5 and Gly are alternately arranged with 3-fold rotational symmetry, coordinated with Fe(II) to form a 1:1 octahedral Fe(II)-peptide complex with a single facial-Λ configuration of the metal-centered chirality. NMR spectroscopy and molecular dynamics simulations revealed that the Fe(II)-peptide complex has an apparent C3-symmetric conformations on the NMR time scale, while the peptide backbone is subject to dynamic conformational exchange between three asymmetric β/γ conformations and one C3-symmetric γ/γ/γ conformation. The semirigid cyclic hexapeptide preferentially arranged these conformations of the small octahedral Fe(II)-bipyridine complex, as well as the Ru(II) congener, to underpin the single configuration of the metal-centered chirality.

The atypical chemokine receptor 3 (ACKR3)/CXC chemokine receptor 7 (CXCR7) recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and is involved in a number of physiological and pathological processes. Here, we investigated the SAR of the component amino acids in an ACKR3-selective ligand, FC313 [ cyclo(-d-Tyr-l-Arg-l-MeArg-l-Nal(2)-l-Pro-)], for the development of highly active ACKR3 ligands. Notably, modification at the l-Pro position with a bulky hydrophobic side chain led to improved bioactivity toward ACKR3.

We recently reported a structure-activity relationship study of 4-epi-jaspine B derivatives toward sphingosine kinase (SphK) and identified selective inhibitors of two SphK isoforms. In this study, we designed and synthesized jaspine B regioisomers on the basis of palladium-catalyzed tetrahydrofuran formation and late-stage cross metathesis reactions to investigate the influence of the substitution position of functional groups on SphK inhibition. Evaluation of the jaspine B regioisomers SphK inhibitory activities revealed that several of these compounds exhibited comparable SphK1/2 inhibitory potency to that of 4-epi-jaspine B.

Stereocalpin A is a cyclic depsipeptide with cytotoxic activity isolated from the Antarctic lichen Stereocaulon alpinum. Although a number of synthetic investigations of the unprecedented 12-membered macrocycle of stereocalpin A with a dipeptide segment and a polyketide substructure have been conducted, the configurational assignment has not been completed. In this study, we achieved the first total synthesis and stereochemical revision of stereocalpin A. To facilitate the comprehensive assessment of eight possible stereocalpin A isomers, four stereoisomers of polyketide precursors were conjugated with l-Phe-l-MePhe and d-Phe-d-MePhe dipeptides (MePhe: N-methylphenylalanine) to provide four possible isomers and four mirror-image structures of the remaining isomers, respectively. The comparative NMR analysis of a series of stereoisomers revealed that stereocalpin A possesses 2 R,4 S,5 R-configurations, which is unique among the related 12-membered hybrid peptide-polyketide natural products reported recently. The NOE correlations in the polyketide substructure of stereocalpin A were also retrospectively analyzed among the eight possible stereoisomers.

Cascade reactions (also represented as domino reactions) realize the step-economical direct construction of natural product core structures. The use of atom-economical elementary reactions in cascade processes can minimize waste production and avoid prefunctionalization of the substrates. Palladium catalysis, which promotes a variety of atom-economical elementary reactions, has long been used as a powerful approach to the direct formation of complex heterocycles. In this short review, palladium-catalyzed cascade reactions for the construction of core structures of natural products reported in the last decade­ are highlighted.1 Introduction2 Reactions Terminated with Heteronucleophiles2.1 Termination with Nitrogen Nucleophiles2.2 Termination with Oxygen Nucleophiles3 Reactions Terminated with Carbon Functional Groups3.1 Termination with Carbon Nucleophiles3.2 Termination with Heck-Type Reactions4 Conclusion

The gold-catalysed annulation of conjugated alkynes bearing an azido group with arenes gave annulated [c]carbazoles. Using benzene, pyrrole, and indole derivatives as the nucleophiles, benzo[c]-, pyrrolo[2,3-c]-, and indolo[2,3-c]carbazoles were produced, respectively. The reaction proceeded through pyrrole and benzene ring construction accompanied by the formation of two carbon–carbon and one carbon–nitrogen bond and the cleavage of two aromatic C–H bonds. The mechanism of the reaction with pyrrole was investigated by density functional theory calculations. N,N′-dimethylated indolo[2,3-c]carbazole showed dual ultraviolet-visible-near-infrared and fluorescence spectral changes upon electrolysis.

Because benzannulated and indole-fused medium-sized rings are found in many bioactive compounds, combining these fragments might lead to unexplored areas of biologically relevant and uncovered chemical space. Herein is shown that α-imino gold carbene chemistry can play an important role in solving the difficulty in the formation of medium-sized rings. Namely, phenylene-tethered azido-alkynes undergo arylative cyclization through the formation of a gold carbene intermediate to afford benzannulated indole-fused medium-sized tetracycles. The reactions allow a range of different aryl substitution patterns and efficient access to these otherwise difficult-to-obtain medium-sized rings. This study also demonstrates the feasibility of the semihollow-shaped C-dtbm ligand for the construction of a nine-membered ring.

Mirror-image screening using d -proteins is a powerful approach to provide mirror-image structures of chiral natural products for drug screening. During the course of our screening study for novel MDM2–p53 interaction inhibitors, we identified that NPD6878 (R-(−)-apomorphine) inhibited both the native l -MDM2– l -p53 interaction and the mirror-image d -MDM2– d -p53 interaction at equipotent doses. In addition, both enantiomers of apomorphine showed potent inhibitory activity against the native MDM2–p53 interaction. In this study, we investigated the inhibitory mechanism of both enantiomers of apomorphine against the MDM2–p53 interaction. Achiral oxoapomorphine, which was converted from chiral apomorphines under aerobic conditions, served as the reactive species to form a covalent bond at Cys77 of MDM2, leading to the inhibitory effect against the binding to p53.

Total synthesis of dictyodendrins A–E was achieved on the basis of a novel gold-catalyzed cascade reaction for the construction of pyrrolo[2,3-c]carbazole scaffold. The synthetic strategy features functionalization of pyrrole pyrrolo[2,3-c]carbazole scaffold at the C1 (arylation), C2 (acylation), N3 (alkylation), and C5 (oxidation) positions. This synthetic method could be used for the diversity-oriented synthesis of dictyodendrin derivatives for medicinal applications.

Grb2 is an adaptor protein that mediates cellular signal transduction. Grb2 contains an SH2 domain that interacts with phosphotyrosine-containing sequences in EGFR and other signaling molecules, and it is a promising molecular target for anticancer agents. To identify novel inhibitors of the Grb2 SH2 domain from natural products and their mirror-image isomers, screening systems using both enantiomers of a synthetic Grb2 SH2 domain protein were established. A pair of synthetic procedures for the proteins were investigated: one employed a single native chemical ligation (NCL) of two segment peptides, and the other used the N-to-C-directed NCL of three segment peptides for easier preparation. Labeling at the N-terminus or the Ala115 residue of the Grb2 SH2 domain provided functional probes to detect binding to a phosphotyrosine-containing peptide. The resulting synthetic-protein-based probes were applied to bioassays, including chemical array analysis and enzyme-linked immunosorbent assays.

Successful gene silencing by small interfering RNA (siRNA) requires efficient uptake of siRNA into targeted cells. For in vitro transfection of siRNA using cationic liposomes, two types of transfection method are currently being used: conventional (forward; Fw) and reverse (Rev) transfections. Here, to investigate an efficient siRNA transfection method using cationic liposomes, we compared the transfection efficiency of siRNA between Fw-transfection and Rev-transfection methods with various types of cationic liposomes. In Fw-transfection, siRNA/cationic liposomes complex (siRNA lipoplexes) was added to pre-plated cells. In contrast, Rev-transfection was performed by co-incubation of cells with siRNA lipoplexes in suspension. As a result, Rev-transfection with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based or cationic cholesterol derivative-based liposomes could deliver siRNA into the cells via efficient cellular association, and induce an improved gene silencing effect by siRNA compared with Fw-transfection. Furthermore, Rev-transfection did not show increased cytotoxicity compared with Fw-transfection. These findings suggested that Rev-transfection in suspension has better potential for efficient transfection of siRNA into cells with minimal toxicity.

The Src SH2 domain was synthesized via native chemical ligation of two fragment peptides. The facile protocol was used to prepare the mirror-image SH2 domain (D-Src SH2 domain) and tetramethylrhodamine-labeled SH2 domains. The synthesized SH2 domains were correctly folded and showed activity, and using these proteins we established bioassays to identify novel Src SH2 domain inhibitors from an unexplored mirror-image library of natural products.

This paper examines the equilibrium growth rate of capital stock and social welfare under an infinite-horizon economy with productivity shocks. The analysis is conducted in an international context where the volatility of production is assumed to be endogenously determined by the degree of market integration. The evidence suggests that when risk aversion is high, endogenous productivity risks can induce precautionary savings and the over-accumulation of capital stock, whereas spillovers from integrated markets are conducive to the under-accumulation of capital stock. Only in this case does a unique equilibrium exist in which partial market integration contributes to growth and social welfare. When risk aversion is low, there exist multiple equilibria depending on the degree of market integration, and full market integration is desirable for social welfare. The model gives an explanation of the withdrawal of the United Kingdom from the European Union as an example of rational market participation decisions.

The risk of infectious diseases caused by Flavivirus is increasing globally. Here, we developed a novel high-throughput screening (HTS) system to evaluate the inhibitory effects of compounds targeting the nuclear localization of the flavivirus core protein. We screened 4000 compounds based on their ability to inhibit the nuclear localization of the core protein, and identified over 20 compounds including inhibitors for cyclin dependent kinase and glycogen synthase kinase. The efficacy of the identified compounds to suppress viral growth was validated in a cell-based infection system. Remarkably, the nucleolus morphology was affected by the treatment with the compounds, suggesting that the nucleolus function is critical for viral propagation. The present HTS system provides a useful strategy for the identification of antivirals against flavivirus by targeting the nucleolar localization of the core protein.

We achieved direct construction of the common pyrrolo[2,3

The X-linked inhibitor of apoptosis protein baculovirus IAP repeat (XIAP BIR3) domain is a promising therapeutic target for cancer treatment. For the mirror-image screening campaign to identify drug candidates from an unexplored mirror-image natural product library, a facile synthetic protocol for XIAP BIR3 domain synthesis was established by a native chemical ligation strategy using conserved cysteines present among BIR domains. The native and mirror-image XIAP BIR3 domains with an appropriate functional group for labeling were prepared using the established protocol. Taking advantage of the resulting synthetic proteins, several bioassay systems were developed to characterize inhibitors of the protein–protein interaction between the XIAP BIR3 domain and the second mitochondria-derived activator of caspases.

Mouse mothers transfer metabolic mode Obesity and metabolic diseases tend to go together, and humans who become obese are also prone to type 2 diabetes and cardiovascular problems. Starting with the observation that offspring of germ-free mice tended to become obese on high-fat diets, Kimura et al. investigated how the presence of the microbiota might be protective in mice (see the Perspective by Ferguson). Short-chain fatty acids (SCFAs) from the microbiota are known to suppress insulin signaling and reduce fat deposition in adipocytes. Further experiments showed that SCFAs in the bloodstream were able to pass from a non–germ-free mother's gut microbiota across the placenta and into the developing embryos. The authors found that in the embryos, the SCFA propionate mediates not only insulin levels through GPR43 signaling but also sympathetic nervous system development through GPR41 signaling. A high-fiber diet promoted propionate production from the maternal microbiota, and maternal antibiotic treatment resulted in obese-prone offspring. Science , this issue p. eaaw8429 ; see also p. 978

The neurokinin B (NKB)-neurokinin-3 receptor (NK3R) signaling positively regulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The NK3R-selective antagonists may suppress the reproductive functions of mammals. For development of novel NK3R antagonists with reduced environmental toxicity, a structure-activity relationship study of an NK3R antagonist, talnetant, was carried out. Among several talnetant derivatives with labile functional groups in the natural environment, 3-mercaptoquinoline 2f exhibited a comparable biological activity to that of the parent talnetant. Additionally, compound 2f was converted into the disulfide 3f or isothiazolone 8 by air-oxidation, both of which showed no binding affinity to NK3R.