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Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson’s disease psychosis, pimavanserin (1), a 5-HT2Areceptor inverse agonist having minimal 5-HT2Creceptor affinity and no dopamine D2receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2Aand 5-HT2Creceptor inverse agonist 8having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2Aand 5-HT2Creceptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2Aand 5-HT2Coccupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2Caffinity in 1followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8that showed significant antipsychotic efficacy due to the involvement of both receptors.

ABSTRACTPotato is the most important non-grain food crop in the world. Viruses, particularly potato virus Y (PVY) and potato virus A (PVA), are among the major agricultural pathogens causing severe reduction in potato yield and quality worldwide. Virus infection induces host factors to interfere with its infection cycle. Evaluation of these factors facilitates the development of intrinsic resistance to plant viruses. In this study, a small G-protein as one of the critical signaling factors was evaluated in plant response to PVY and PVA to enhance resistance. For this purpose, the gene expression dataset of G-proteins in potato plant under five biotic (viruses, bacteria, fungi, nematodes, and insects) and four abiotic (cold, heat, salinity, and drought) stress conditions were collected from gene expression databases. We reduced the number of the selected G-proteins to a single protein, StSAR1A, which is possibly involved in virus inhibition. StSAR1Aoverexpressed transgenic plants were created via the Agrobacterium-mediated method. Real-time PCR and Enzyme-linked immunosorbent assay tests of transgenic plants mechanically inoculated with PVY and PVA indicated that the overexpression of StSAR1Agene enhanced resistance to both viruses. The virus-infected transgenic plants exhibited a greater stem length, a larger leaf size, a higher fresh/dry weight, and a greater node number than those of the wild-type plants. The maximal photochemical efficiency of photosystem II, stomatal conductivity, and net photosynthetic rate in the virus-infected transgenic plants were also obviously higher than those of the control. The present study may help to understand aspects of resistance against viruses.

Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer’s disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5achieved sustained Aβ reduction of 80% at trough level.

BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer’s disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21and 22. The structures of 22bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622exhibited antiviral activity in vitroagainst current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivofor once-daily oral dosing. Furthermore, S-217622dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

Plants and animals can recognize the invasion of pathogens through their perception of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Plant PRRs identified have been exclusively receptor-like kinases/proteins (RLK/Ps), and no RLK/P that can detect viruses has been identified to date. RNA silencing (RNA interference, RNAi) is regarded as an antiviral basal immunity because the majority of plant viruses has RNA as their genomes and encode RNA silencing suppressor (RSS) proteins to counterattack antiviral RNAi. Many RSSs were reported to bind to double-stranded RNAs (dsRNAs), which are regarded as viral PAMPs. We have recently identified a tobacco calmodulin (CaM)-like protein, rgs-CaM, as a PRR that binds to diverse viral RSSs through its affinity for the dsRNA-binding domains. Because rgs-CaM seems to target RSSs for autophagic degradation with self-sacrifice, the expression level of rgs-CaM is important for antiviral activity. Here, we found that the rgs-CaM expression was induced immediately (within 1 h) after wounding at a wound site on tobacco leaves. Since the invasion of plant viruses is usually associated with wounding, and several hours are required for viruses to replicate to a detectable level in invaded cells, the wound-induced expression of rgs-CaM seems to be linked to its antiviral function, which should be ready before the virus establishes infection. CaMs and CaM-like proteins usually transduce calcium signals through their binding to endogenous targets. Therefore, rgs-CaM is a unique CaM-like protein in terms of binding to exogenous targets and functioning as an antiviral PRR.

Facile and efficientmacrolactonization of hydroxycarboxylic acid via ethoxyvinyl esters (EVEs), which can give 9‐ to 14‐membered macrolactones in good yields, has been developed (see scheme; DCE = 1,2‐dichloroethane). The method is useful for acid‐/base‐sensitive substrates and applicable to the compound with many functional groups.

The effect of TiC content on oxidation behavior of the sintered WC-TiC-TaC alloys with 2 mass% TaC and different TiC amount of 3-45 mass% was investigated through oxidation tests in air at 973K in order to clarify their oxidation mechanism at high temperature. Based on the results of mass change, SEM observation, elemental map analysis and composition analysis of the samples before and after the oxidation test, it was revealed that with increasing TiC content in the alloys, mass changes from oxidation and thickness of the oxidation scale decreased. Thus, it is considered that the main component of the scales changed from WO3 to TiO2 gradually with increasing TiC content in the alloys, and oxygen diffusing through the oxidation scale to the alloys was inhibited more and more.

Postovulatory aging of oocytes significantly affects embryonic development. Also, altered Ca2+oscillation patterns can be observed in fertilized, aged mouse oocytes. Because Ca2+oscillations depend on Ca2+release and reuptake in the endoplasmic reticulum, and the latter relies on ATP availability, we simultaneously measured changes in intracellular ATP concentration ([ATP]i) and Ca2+oscillations in fresh and aged mouse oocytes. We continuously assessed changes in [ATP]ifrom intracellular free Mg2+concentration measured by fluorescent dye Magnesium Green (MgG) while intracellular Ca2+concentration ([Ca2+]i) was monitored by Fura-PE3. At fertilization, MgG fluorescence was transiently increased concomitant with the first transient elevation in [Ca2+]i, indicating a relative decrease in [ATP]i. In fresh oocytes, it was quickly followed by a significant decrease below baseline, indicating a relative increase in [ATP]i. In contrast, in aged oocytes, such a decrease in MgG fluorescence was not observed. In a separate experiment, ATP content in fresh and aged oocytes was determined in vitro by the luciferin-luciferase assay. Intracellular ATP contents measured in vitro were comparable in unfertilized fresh and aged oocytes. Intracellular ATP content at 5 h after fertilization was increased in both oocytes, where fresh oocytes showed a significantly higher intracellular value than aged oocytes. These findings suggest that aged mouse oocytes fail to readjust the level of intracellular ATP at fertilization. Relative deficiencies of ATP at fertilization might lead to an altered Ca2+oscillation pattern and poor developmental potency, which is commonly noted in aged oocytes.

Although it is well known that the uterine cervix contains mucin-producing glandular epithelium, only a few studies have described the changes in mucin that accompany malignant transformation. In this study the authors evaluated the characteristics of mucin expression in the normal endocervical epithelium and mucinous and endometrioid adenocarcinomas of the uterine cervix. The normal endocervical epithelium was characterized by predominant sulfomucin and MUC1 expression in all sites and MUC5AC expression in the surface epithelium, while MUC2 was not detected at all and pyloric gland type mucin (using antibody HIK1083) was detected in less than 1 of cases. Cervical adenocarcinomas, especially mucinous adenocarcinomas, showed marked variability in mucin expression that included mucins of pyloric gland and intestinal type.

Nucleic acid sequence‐based amplification (NASBA) according to the standard protocol failed to amplify cRNA of viroids, probably because of their GC‐rich and intramolecular base‐paired structure. However, NASBA in the presence of inosine 5′‐triphosphate successfully amplified the cRNAs to viroids in total nucleic acid extracts from citrus plants. As sequence specificity of the cRNA to viroids was confirmed by northern analysis, the amplification and fidelity of cRNAs are sufficient for the sensitive and specific detection of viroids.

Chiral spiroketals (II), (VI) and (IX) are synthesized based on remote asymmetric induction.

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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

In this paper we proposes a reference cell with variable spectral response characteristics to be used for measurement of various rypes of solar cells, and describe the design and experimental manufacturing of such a reference cell. The reference cell consists of a c-Si cell, a filter wheel mounted with 15 sharp cut-off filters, and a computer. In this system, characteristic synthesis of output light signals through each filter is done rapidly by the computer, thus realizing a cell having arbitrary characteristics. The composite wavelength ranges from 320 nm to 850 nm with a minimum control width of 40 nm. This system can function as 5 reference cells simultaneously, and has a continuous display with the response rate of once per second. The accuracy of measurement was within ±2%, which proves the practicality of the system.