RESUMO
Disentangling the roles of nitrogen dopants and vacancy defects (VG) in metal-free carbon catalysts for the oxygen reduction reaction (ORR) ideally requires studying both the dopants and defects separately. Here, we systematically introduced nitrogen dopants and VGs via plasma treatment into the basal plane of monolayer graphene as a model carbon catalyst to investigate their specific roles in ORR catalysis. An increased defect density including dopants is positively associated with boosted ORR activity. Nitrogen dopants are responsible for an improved current via a 2e- pathway generating hydroperoxide, while VGs result in enhanced kinetics and water production. We therefore infer that VGs in graphene are responsible for the improved ORR kinetics, while nitrogen dopants majorly influence the selectivity of ORR reaction products. The nitrogen dopants without VGs lead to a higher overpotential compared with the pristine graphene. Instead of the attribution of the ORR active site to only nitrogen species in carbon materials, the improved ORR activity in nitrogen-doped carbon materials should be attributed to the active sites constituted of VGs, oxygen dopants, and nitrogen dopants. Through this work, we provide important insights into the intertwined roles of nitrogen and VGs as well as oxygen dopants in nitrogen-doped metal-free catalysts for a more efficient ORR.
RESUMO
Polymeric materials play a pivotal role in our modern world, offering a diverse range of applications. However, they have been designed with end-properties in mind over recyclability, leading to a crisis in their waste management. The recent emergence of electrochemical recycling methodologies for polymeric materials provides new perspectives on closing their life cycle, and to a larger extent, the plastic loop by transforming plastic waste into monomers, building blocks, or new polymers. In this context, we summarize electrochemical strategies developed for the recovery of building blocks, the functionalization of polymer chains as well as paired electrolysis and discuss how they can make an impact on plastic recycling, especially compared to traditional thermochemical approaches. Additionally, we explore potential directions that could revolutionize research in electrochemical plastic recycling, addressing associated challenges.
RESUMO
The BL17B beamline at the Shanghai Synchrotron Radiation Facility was first designed as a versatile high-throughput protein crystallography beamline and one of five beamlines affiliated to the National Facility for Protein Science in Shanghai. It was officially opened to users in July 2015. As a bending magnet beamline, BL17B has the advantages of high photon flux, brightness, energy resolution and continuous adjustable energy between 5 and 23â keV. The experimental station excels in crystal screening and structure determination, providing cost-effective routine experimental services to numerous users. Given the interdisciplinary and green energy research demands, BL17B beamline has undergone optimization, expanded its range of experimental methods and enhanced sample environments for a more user-friendly testing mode. These methods include single-crystal X-ray diffraction, powder crystal X-ray diffraction, wide-angle X-ray scattering, grazing-incidence wide-angle X-ray scattering (GIWAXS), and fully scattered atom pair distribution function analysis, covering structure detection from crystalline to amorphous states. This paper primarily presents the performance of the BL17B beamline and the application of the GIWAXS methodology at the beamline in the field of perovskite materials.
RESUMO
BL19U1, an energy-tunable protein complex crystallography beamline at the Shanghai Synchrotron Radiation Facility, has emerged as one of the most productive MX beamlines since opening to the public in July 2015. As of October 2023, it has contributed to over 2000 protein structures deposited in the Protein Data Bank (PDB), resulting in the publication of more than 1000 scientific papers. In response to increasing interest in structure-based drug design utilizing X-ray crystallography for fragment library screening, enhancements have been implemented in both hardware and data collection systems on the beamline to optimize efficiency. Hardware upgrades include the transition from MD2 to MD2S for the diffractometer, alongside the installation of a humidity controller featuring a rapid nozzle exchanger. This allows users to opt for either low-temperature or room-temperature data collection modes. The control system has been upgraded from Blu-Ice to MXCuBE3, which supports website-mode data collection, providing enhanced compatibility and easy expansion with new features. An automated data processing pipeline has also been developed to offer users real-time feedback on data quality.
RESUMO
BACKGROUND: Cryptosporidiosis and giardiasis are significant parasitic diseases shared between humans and domestic animals. Due to the close contact between humans and domestic animals in rural areas, it is important to consider the potential transmission of zoonotic parasites from infected domestic animals to humans. This investigation aimed to determine the prevalence and molecular characteristics of Cryptosporidium spp. and Giardia duodenalis in domestic animals and villagers. METHODS: A total of 116 fecal samples from villagers and 686 fecal samples from domestic animals in Heilongjiang Province, China, were analyzed for two parasites using nested polymerase chain reaction (PCR) targeting various genetic loci and DNA sequence analysis of the PCR products. RESULTS: By sequence analysis of the SSU rRNA gene, the prevalence of Cryptosporidium in humans was 0.9% (1/116), with one species of C. parvum (n = 1) detected; among domestic animals, the prevalence was 2.6% (18/686), with five species identified: C. suis (n = 7) and C. scrofarum (n = 7) in pigs, C. meleagridis (n = 1) in chickens, C. andersoni (n = 1) in cattle, and C. canis (n = 2) in foxes. C. parvum and C. canis were further subtyped as IIdA19G1 and XXa4 on the basis of gp60 gene. Regarding G. duodenalis, based on the SSU rRNA, bg, gdh, and tpi genes, the prevalence in domestic animals was 5.1% (31/608), with three assemblages identified: A (n = 1) in pigs, D (n = 1) in foxes, and E (n = 27) in geese, cattle, pigs, ducks, and sheep, along with mixed infection of A + E (n = 1) in one pig and B + E (n = 1) in one sheep. No G. duodenalis was detected in humans (0/116). CONCLUSIONS: The present results show that no overlap of subtypes between animals and villagers was found in Cryptosporidium spp. and G. duodenalis, indicating a minor role of domestic animals in infecting humans in this population. However, the presence of zoonotic protozoa in domestic animals highlights the need for special attention to high-risk individuals during close contact with domestic animals.
Assuntos
Criptosporidiose , Cryptosporidium , Giardia lamblia , Giardíase , Humanos , Animais , Bovinos , Ovinos , Suínos , Giardia lamblia/genética , Criptosporidiose/epidemiologia , Criptosporidiose/parasitologia , Cryptosporidium/genética , Animais Domésticos , Raposas , Galinhas , Giardíase/epidemiologia , Giardíase/veterinária , Giardíase/parasitologia , China/epidemiologia , Fezes/parasitologia , Prevalência , GenótipoRESUMO
Background: Clonorchiasis is an important foodborne parasitic disease. However, eggs of Clonorchis sinensis (C. sinensis) cannot be detected in feces during biliary obstruction. Moreover, many diseases can cause biliary obstruction, such as gallstones, adenocarcinoma, cholangiocarcinoma and Ascaris lumbricoides infection. Therefore, it is of great significance to distinguish between patients of biliary obstruction and biliary obstruction with C. sinensis infection. Methods: A total of 48 biliary obstruction patients were enrolled, including 23 infected with C. sinensis (C. sinensis) (OB+C.s) and 25 non-infected subjects (OB). The bile samples were collected by endoscopic retrograde cholangiopancreatography and analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Additionally, multivariate statistical analysis methods were employed to identify differential metabolites. Next, bile amino acid levels were determined by targeted metabolomics analysis. Result: A total of 146 and 132 significant metabolites were identified in electrospray ionization (ESI)+ and ESI- modes, respectively. The levels of amino acids (asparagine, glutamate, ornithine) and polyamines (spermidine and spermine) were significantly changed. Targeted analysis showed that the levels of amino acids (such as L-arginine, L-glutamine, L-lysine, L-propionic, and L-tyrosine) were lower in OB+C.s patients compared to those in OB patients. Marked metabolic pathways were involved in "Glutathione metabolism", "Caffeine metabolism", "Alanine, aspartate and glutamate metabolism", "Arginine and proline metabolism", "Purine metabolism", "Beta-Alanine metabolism", and "D-glutamine and D-glutamate metabolism". Conclusion: These results show that there were significant differences between OB+C.s and OB patients, especially in amino acids. The metabolic signature and perturbations in metabolic pathways may help to better distinguish OB+C.s and OB patients.
Assuntos
Colestase , Clonorquíase , Clonorchis sinensis , Animais , Humanos , Clonorquíase/complicações , Clonorquíase/parasitologia , Bile/química , Bile/metabolismo , Bile/parasitologia , Clonorchis sinensis/metabolismo , Colestase/complicações , Colestase/metabolismo , Aminoácidos/metabolismo , Glutamina/metabolismo , Metaboloma , Glutamatos/análise , Glutamatos/metabolismoRESUMO
The hydrostatic bearing slipper pair of the hydraulic pump has a unique adaptive friction characteristic, which has a better friction reduction and anti-wear ability than the general sliding friction pair, and also has a certain recovery effect on the performance degradation caused by the early wear of the slipper. This paper attempts to reveal the friction adaptive mechanism. Based on the fractal theory, two fractal parameters of fractal dimension and scale coefficient are used to characterize the surface morphology of the slipper mathematically, and the adaptive friction mechanism model is established by combining the friction coefficient equation. The effects of different fractal parameters on the friction coefficient and other performance parameters of slipper pairs are obtained by means of the numerical analysis method. The wear test was carried out by replacing specimens at different intervals to observe the worn surface morphology and the degradation process of the slipper to verify the correctness of the theoretical results. The results show that the friction performance and load-bearing capabilities of the slipper can be recovered to a certain extent within a short period when early wear occurs, and its surface performance shows the variation characteristics of deterioration-repair-re-deterioration-re-repair.
RESUMO
Since severe global warming and related climate issues have been caused by the extensive utilization of fossil fuels, the vigorous development of renewable resources is needed, and transformation into stable chemical energy is required to overcome the detriment of their fluctuations as energy sources. As an environmentally friendly and efficient energy carrier, hydrogen can be employed in various industries and produced directly by renewable energy (called green hydrogen). Nevertheless, large-scale green hydrogen production by water electrolysis is prohibited by its uncompetitive cost caused by a high specific energy demand and electricity expenses, which can be overcome by enhancing the corresponding thermodynamics and kinetics at elevated working temperatures. In the present review, the effects of temperature variation are primarily introduced from the perspective of electrolysis cells. Following an increasing order of working temperature, multidimensional evaluations considering materials and structures, performance, degradation mechanisms and mitigation strategies as well as electrolysis in stacks and systems are presented based on elevated temperature alkaline electrolysis cells and polymer electrolyte membrane electrolysis cells (ET-AECs and ET-PEMECs), elevated temperature ionic conductors (ET-ICs), protonic ceramic electrolysis cells (PCECs) and solid oxide electrolysis cells (SOECs).
RESUMO
Blastocystis is an enteric protozoan able to infect humans and a large variety of animal hosts worldwide. It exhibits significant genetic diversity, with at least 17 subtypes (STs) identified to date, most of which have low host specificity. In the present study, a cross-sectional survey was conducted on Blastocystis infection among humans and domestic animals sharing habitats in northeastern China's Heilongjiang Province, in order to investigate the frequency and subtype distribution and to evaluate the risk of the zoonotic transmission of Blastocystis sp..Results show that the frequency was 10.5% (6/57), and three subtypes (ST1, ST2, and ST3) were found in humans; in animals, the frequency was 17.9% (46/257), and six subtypes (ST1, ST3, ST5, ST7, ST10, and ST26) were detected. A significant association between Blastocystis sp. infection and eating unwashed vegetables and fruits was found (P = 0.007). We found no effect on gender, age and season on Blastocystis sp. colonization. Phylogenetic analysis showed that Blastocystis ST7 sequences from chicken in two geographical locations formed two distinct clades. Alleles were identified using the Blastocystis 18S database, and a total of 10 different alleles were found in seven STs. Overlap of STs in humans and domestic animals (pig or cattle) was observed in Dongfanghong village. The findings of potentially zoonotic subtypes in domestic animals suggest that these animals may serve as reservoirs of human Blastocystis sp. infections. Multisectoral cooperation is needed to slow down the transmission of Blastocystis in domestic animals, minimize environmental contamination by Blastocystis cysts, and increase molecular epidemiological surveillance of Blastocystis sp. in humans and animals.
Assuntos
Infecções por Blastocystis , Blastocystis , Humanos , Animais , Bovinos , Suínos , Blastocystis/genética , Animais Domésticos , Filogenia , Estudos Transversais , Variação Genética , Infecções por Blastocystis/veterinária , China/epidemiologia , Fezes , PrevalênciaRESUMO
Esophageal squamous cell carcinoma (ESCC) accounts for 90% of esophageal cancers and has a high mortality rate worldwide. The 5-year survival rate of ESCC patients in developing countries is <20%. Hence, there is an urgent need for developing new and effective treatments that are based on newly-discovered emerging molecules and pathways to prevent ESCC occurrence and recurrence. We investigated the effects of Daurisoline, a bis-benzylisoquinoline alkaloid extracted from the rhizome of menisperum dauricum, on ESCC cell proliferation and elucidated the molecular mechanisms underlying its functions. To explore the effects of Daurisoline on ESCC growth in vitro and in vivo, cell proliferation assays and anchorage-independent growth assays were performed and a patient-derived xenograft (PDX) model was established. Subsequently, phosphoproteomics, molecular docking analysis, pull down assays, mutation experiments and in vitro kinase assay were performed to explore the mechanism of Daurisoline's function on ESCC. Daurisoline inhibited ESCC proliferation in vitro and reduced ESCC PDX exnograft growth in vivo by reducing ERK1/2 phosphorylation. Furthermore, it directly bound to MEK1 (at Asn78 and Lys97) and MEK2 (at Asp194 and Asp212) kinases to inactivate the ERK1/2 signaling pathway. Our results suggest that Daurisoline is a dual inhibitor of MEK1 and MEK2 and suppresses ESCC growth both in vitro and in vivo by inactivating the ERK1/2 signaling pathway. This is first report on the use of MEK inhibitor for ESCC and highlights its potential applications for ESCC treatment and prevention.
Assuntos
Benzilisoquinolinas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/genética , Simulação de Acoplamento Molecular , Proliferação de Células , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Benzilisoquinolinas/farmacologia , Regulação Neoplásica da Expressão GênicaRESUMO
The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974-0.991, p = 1.18 × 10-4). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR = 0.981; 95% CI = 0.969-0.993; p = 2.75 × 10-3). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345-2.072; p = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed.
Assuntos
Transtorno Depressivo Maior , Lúpus Eritematoso Sistêmico , Humanos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica Ampla , Causalidade , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
With wide applications of image editing tools, forged images (splicing, copy-move, removal and etc.) have been becoming great public concerns. Although existing image forgery localization methods could achieve fairly good results on several public datasets, most of them perform poorly when the forged images are JPEG compressed as they are usually done in social networks. To tackle this issue, in this paper, a self-supervised domain adaptation network, which is composed of a backbone network with Siamese architecture and a compression approximation network (ComNet), is proposed for JPEG-resistant image forgery detection and localization. To improve the performance against JPEG compression, ComNet is customized to approximate the JPEG compression operation through self-supervised learning, generating JPEG-agent images with general JPEG compression characteristics. The backbone network is then trained with domain adaptation strategy to localize the tampering boundary and region, and alleviate the domain shift between uncompressed and JPEG-agent images. Extensive experimental results on several public datasets show that the proposed method outperforms or rivals to other state-of-the-art methods in image forgery detection and localization, especially for JPEG compression with unknown QFs.
RESUMO
The major facilitator superfamily (MFS) is the largest secondary transporter family and is responsible for transporting a broad range of substrates across the biomembrane. These proteins are involved in a series of conformational changes during substrate transport. To decipher the transport mechanism, it is necessary to obtain structures of these different conformations. At present, great progress has been made in predicting protein structure based on coevolutionary information. In this study, AlphaFold2 was used to predict different conformational structures for 69 MFS transporters of E. coli after the selective mutation of residues at the interface between the N- and C-terminal domains. The predicted structures for these mutants had small RMSD values when compared to structures obtained using X-ray crystallography, which indicates that AlphaFold2 predicts the structure of MSF transporters with high accuracy. In addition, different conformations of other transporter family proteins have been successfully predicted based on mutation methods. This study provides a structural basis to study the transporting mechanism of the MFS transporters and a method to probe dynamic conformation changes of transporter family proteins when performing their function.
Assuntos
Escherichia coli , Proteínas de Membrana Transportadoras , Cristalografia por Raios X , Escherichia coli/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Modelos Moleculares , Mutação , Conformação ProteicaRESUMO
Corona Virus Disease 2019 (COVID-19) has led to an increase in attacks targeting widespread smart devices. A vulnerable device can join multiple botnets simultaneously or sequentially. When different attack patterns are mixed with attack records, the security analyst produces an inaccurate report. There are numerous studies on botnet detection, but there is no publicly available solution to classify attack patterns based on the control periods. To fill this gap, we propose a novel data-driven method based on an intuitive hypothesis: bots tend to show time-related attack patterns within the same botnet control period. We deploy 462 honeypots in 22 countries to capture real-world attack activities and propose an algorithm to identify control periods. Experiments have demonstrated our method's efficacy. Besides, we present eight interesting findings that will help the security community better understand and fight botnet attacks now and in the future.
RESUMO
BACKGROUND: Giardia duodenalis is a common parasitic diarrheal agent in humans, especially in developing countries. The aim of this study was to investigate the prevalence and multilocus genetic characterization of G. duodenalis in patients with diarrhea and animals in northeastern China, and to assess the epidemiological role of animals in the transmission of human giardiasis. METHODS: A total of 1739 fecal specimens from 413 diarrheal patients and 1326 animals comprising 16 mammal species were collected in Heilongjiang Province of China and screened for G. duodenalis by PCR and sequencing of the SSU rRNA gene. All G. duodenalis-positive specimens were subtyped by PCR and sequencing of the bg, tpi, and gdh genes. To detect additional mixed infections of different assemblages, assemblage A/B/E-specific PCRs were performed to amplify the tpi gene. RESULTS: Sequence analysis of the SSU rRNA gene determined the prevalence of G. duodenalis (5.81%, 24/413) in diarrheal patients, with a peak in minors aged 5-17 years, and identified assemblages A and B. MLG-AII and MLG-B1 were obtained based on concatenated nucleotide sequences of the bg, tpi, and gdh genes, with MLG-AII being identical to a cat-derived isolate reported previously. By sequence analysis of the SSU rRNA gene, G. duodenalis was detected in 214 (16.14%) animals belonging to 11 mammal species, with the prevalence ranging from 1.69 to 53.85%, and assemblages A to G were identified. Sequence analysis of the bg, tpi, and gdh genes from 46 specimens produced 31 MLGs, including MLG-AI (n = 1), MLG-B2-B8 (n = 18), and MLG-E1-E23 (n = 27). CONCLUSIONS: The finding of G. duodenalis in diarrheal patients enhances consciousness of detecting G. duodenalis in clinical practice and emphasizes the importance of health education in local inhabitants, especially in the age group of 5-17 years. The identification of seven assemblages (A to G) and 33 MLGs reveals genetic heterogeneity of G. duodenalis in the investigated areas. Due to insufficient homology data on the zoonotic transmission of G. duodenalis, the precise epidemiological role that animals play in the transmission of human giardiasis needs to be assessed by more large-scale molecular epidemiological investigations of local humans and animals.
Assuntos
Giardia lamblia , Giardíase , Animais , China/epidemiologia , Diarreia/epidemiologia , Fezes/parasitologia , Genótipo , Giardíase/epidemiologia , Giardíase/parasitologia , Giardíase/veterinária , Humanos , Mamíferos/genética , Tipagem de Sequências Multilocus , PrevalênciaRESUMO
Zinc peptidase M16 family members are widely distributed in most prokaryotic and eukaryotic organisms. M16 family has been divided into three subfamilies, M16A, M16B and M16C, based on sequence alignments and subunit connectivity. TTHA1264, an M16B protein found in Thermus thermophiles HB8, possesses an HXXEH motif essential for Zn2+ binding and catalytic activity. TTHA1265 is another member of M16B, which lacks the metal-binding motif but with a conserved active-site R/Y pair commonly found in the C-terminal half of M16 enzymes. Sequence analysis showed that two genes coding for TTHA1264 and TTHA1265 assemble into a single operon in the bacterial genome. Here, we report the crystal structure of TTHA1265 and TTHA1264/TTHA1265 complex from T. thermophilus HB8. Interestingly, when TTHA1264 and TTHA1265 are present alone, TTHA1264 forms a monomer, TTHA1265 forms a homodimer, respectively. However, TTHA264 and TTHA1265 assembled into a heterodimeric complex, indicating that they prefer to form heterodimer. Biochemical data further confirmed the heterodimeric assembly indicating intrinsic heterodimeric assembly of TTHA1264 and TTHA1265. This property of TTHA1264 and TTHA1265 is consistent with the characteristics of the M16B family.
Assuntos
Proteínas de Bactérias , Sequência de Aminoácidos , Proteínas de Bactérias/química , Sítios de Ligação , Cristalografia por Raios X , Homologia de Sequência de AminoácidosRESUMO
MreC is a scaffold protein required for cell shape determination through interactions with proteins related to cell wall synthesis. Here, we determined the crystal structure of the major periplasmic part of MreC from Escherichia coli at 2.1 Å resolution. The periplasmic part of MreC contains a coiled-coil domain and two six-stranded barrel domains. The coiled-coil domain is essential for dimer formation, and the two monomers are prone to relative motion that is related to the small interface of ß-barrel domains. In addition, MreC forms an antiparallel filament-like structure along the coiled-coil direction, which is different from the helical array structure in Pseudomonas aeruginosa. Our structure deepens our understanding of polymer formation of MreC.
Assuntos
Proteínas de Bactérias , Polímeros , Proteínas de Bactérias/química , Domínios Proteicos , Pseudomonas aeruginosaRESUMO
Insecure applications (apps) are increasingly used to steal users' location information for illegal purposes, which has aroused great concern in recent years. Although the existing methods, i.e., static and dynamic taint analysis, have shown great merit for identifying such apps, which mainly rely on statically analyzing source code or dynamically monitoring the location data flow, identification accuracy is still under research, since the analysis results contain a certain false positive or true negative rate. In order to improve the accuracy and reduce the misjudging rate in the process of vetting suspicious apps, this paper proposes SAMLDroid, a combined method of static code analysis and machine learning for identifying Android apps with location privacy leakage, which can effectively improve the identification rate compared with existing methods. SAMLDroid first uses static analysis to scrutinize source code to investigate apps with location acquiring intentions. Then it exploits a well-trained classifier and integrates an app's multiple features to dynamically analyze the pattern and deliver the final verdict about the app's property. Finally, it is proved by conducting experiments, that the accuracy rate of SAMLDroid is up to 98.4%, which is nearly 20% higher than Apparecium.
RESUMO
Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization.IMPORTANCE Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Therefore, there is an urgent need for broad-spectrum inhibitors to address the considerable challenges posed by the rapid evolution of influenza viruses that limit the effectiveness of vaccines and lead to the emergence of antiviral drug resistance. Here, we identified a novel influenza A virus NP antagonist, FA-6005, with broad-spectrum efficacy against influenza viruses, and our study presents a comprehensive study of the mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza virus inhibitor holds promise as an urgently sought-after therapeutic option offering a mechanism of action complementary to existing antiviral drugs for the treatment of influenza virus infection and should further aid in the development of universal therapeutics.
Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Proteínas do Nucleocapsídeo , Replicação Viral/efeitos dos fármacos , Animais , Cães , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/antagonistas & inibidores , Proteínas do Nucleocapsídeo/metabolismo , Infecções por Orthomyxoviridae/prevenção & controle , Ligação ProteicaRESUMO
ß-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-ß-lactamase 1 (NDM-1) is able to hydrolyze nearly all ß-lactam antibiotics and even clinically used serine-ß-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.