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1.
    
Rapid emergence of multidrug resistant Staphylococcus aureus infections has created a critical health menace universally. Resistance to all the available chemotherapeutics has been on rise which led to WHO to stratify Staphylococcus aureus as high tier priorty II pathogen. Hence, discovery and development of new antibacterial agents with new mode of action is crucial to address the multidrug resistant Staphylococcus aureus infections. The egressing understanding of new antibacterials on their biological target provides opportunities for new therapeutic agents. This review underlines on various aspects of drug design, structure activity relationships (SARs) and mechanism of action of various new antibacterial agents and also covers the recent reports on new antibacterial agents with potent activity against multidrug resistant Staphylococcus aureus. This review provides attention on in vitro and in vivo pharmacological activities of new antibacterial agents in the point of view of drug discovery and development.  相似文献   

2.
    
The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik–Fields, Mannich, Arbuzov, Michaelis–Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs.  相似文献   

3.
    
Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX.  相似文献   

4.
    
The rod-outer-segment guanylyl cyclase 1 (ROS-GC1) is a key transmembrane protein for retinal phototransduction. Mutations of ROS-GC1 correlate with different retinal diseases that often lead to blindness. No structural data are available for ROS-GC1 so far. We performed a 3D-structural analysis of native ROS-GC1 from bovine retina by cross-linking/mass spectrometry (XL-MS) and computational modeling. Absolute quantification and activity measurements of native ROS-GC1 were performed by MS-based assays directly in bovine retina samples. Our data present the first 3D-structural analysis of active, full-length ROS-GC1 derived from bovine retina. We propose a novel domain organization for the intracellular domain ROS-GC1. Our XL-MS data of native ROS-GC1 from rod-outer-segment preparations of bovine retina agree with a dimeric architecture. Our integrated approach can serve as a blueprint for conducting 3D-structural studies of membrane proteins in their native environment.  相似文献   

5.
    
Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.  相似文献   

6.
    
Introduction and aimConsidering the magnitude of giardiasis problem, the side-effects of the used anti-giardia drugs and the resistance posed against them, the current study aimed to evaluate the in-vivo giardicidal effect of Psidium guajava leaf extract (PGLE).MethodsFor fulfilling this aim, five Swiss-albino mice groups were included; GI: non-infected, GII: Giardia-infected and non-treated, GIII: Giardia-infected and metronidazole-treated, GIV: Giardia-infected and PGLE-treated, and GV: Giardia-infected and treated with both metronidazole and PGLE. Treatment efficacy was assessed via; Giardia cyst viability and trophozoite count, trophozoite electron microscopic ultrastructure, duodenal histopathological scoring, immunohistochemistry for TNF-α and duodenal scanning electron microscopy. Moreover, mice serum liver enzymes, total bilirubin, albumin, lipid profile including; total cholesterol, HDL, LDL and triglycerides were assessed. Additionally, hepatic oxidative stress markers including; malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured.ResultsResults showed that PGLE whether alone or combined with metronidazole has induced significant trophozoite count reduction and major architectural changes. Duodenal histological improvement, and local protective anti-inflammatory effect were confirmed. PGLE has also helped in healing of Giardia-induced gut atrophy. Thus, offered a comprehensive therapy for both the pathogen and the resultant pathological sequalae. Serum markers showed favorable hepatoprotective effect. Total cholesterol, LDL and triglycerides levels were less in PGLE-treated group than in metronidazole-treated group. Hepatic oxidative stress markers revealed the promising extract antioxidant effect. This study highlights, the promising in-vivo giardicidal PGLE activity, that was comparable to metronidazole, thus, the extract would be an ideal strongly recommended treatment for giardiasis. When combined with metronidazole, the extract potentiated its therapeutic effect. Besides, having hepatoprotective, anti-inflammatory, and antioxidant properties, the extract can combat the major side effects of metronidazole therapy.  相似文献   

7.
    
In pursuit of an environmentally benign fungicide alternative, the current study explored the antifungal activity of Chlorella vulgaris extracts against six plant pathogenic fungi (in vitro). The well diffusion agar method was used to investigate the growth inhibition of Fusarium oxysporum, Fusarium sp., Fusarium solani, A. flavus, A. niger, and A. alternata using the three C. vulgaris extracts viz. methanol (CvME), acetone (CvAE), and diethyl ether (CvDE). Different concentrations of CvDE were also investigated against F. oxysporum. The morphological modifications in F. oxysporum treated with CvDE (5 mg/kg) were studied using SEM and the chemical composition of CvDE was also determined by GC–MS analysis. All extracts, with the exception of A. alternata, were found to be effective in inhibiting the growth of plant pathogenic fungi. The CvDE extract, followed by CvME and CvAE, was found to be efficient against tested fungi. The CvDE was most effective against F. oxysporum with a 73.3% growth inhibition. The effects of various CvDE concentrations on F. oxysporum were found to be dosage dependent. The SEM micrograph revealed that CvDE-treated F. oxysporum had substantially less conidia than the control. The CvDE treatment damaged the mycelial structure as well. Major chemical components detected in CvDE were Heptaldehyde (15.7%), Octadecenoic acid, methyl ester (12.6%), Hexadecanoic acid (12%), 3-Decyn-2-Ol (10.98%), (E)-3,7,11,15-tetramethylhexadec-2-ene (9.76%), heptadecane-1,2,3,4,5-pentol (8.7%), Docosane, 4-methyl (7.28%).  相似文献   

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9.
Poultry production has been developing in Vietnam with challenges of disease. Thus, feed additive should be investigated not only growth but also health enhancement. Here, we aimed to determine the effects of Saccharomyces cerevisiae-fermented rice (FR) and β-glucan on turkey’s growth performance, carcass characteristics, immune and fatty acid (FA) profiles. A total of 180 turkey chicks aged 1–56 days were randomly assigned to five sextuplicate groups and the birds had ad libitum feed and water access throughout the experiment. The five treatment groups were given the same diet with different proportions of FR and β-glucan. Broilers supplemented with 4% β-glucan and 4% FR presented the highest and second-highest growth performance, respectively. The 4% β-glucan and 4% FR treatments resulted in the highest carcass characteristic values without significantly affecting the breast or thigh meat pH or cooking loss. The 4% β-glucan and 4% FR treatments maximally increased the Newcastle disease (ND) antibody titers at 28, 42 and 56 days, respectively as well as thymus organ index. The foregoing treatments did not significantly affect the blood profiles relative to the control. However, the 4% FR treatment lowered the blood cholesterol levels (p > 0.05). The total FA profiles did not significantly differ among treatments. Nevertheless, both the β-glucan and FR treatments increased the MUFA levels compared to that of the control (p > 0.05). Hence, the dietary administration of 4% β-glucan and FR to turkey broilers could effectively improve their growth performance and immunity.  相似文献   

10.
    
The FimH protein of Escherichia coli is a model two-domain adhesin that is able to mediate an allosteric catch bond mechanism of bacterial cell attachment, where the mannose-binding lectin domain switches from an ‘inactive’ conformation with fast binding to mannose to an ‘active’ conformation with slow detachment from mannose. Because mechanical tensile force favors separation of the domains and, thus, FimH activation, it has been thought that the catch bonds can only be manifested in a fluidic shear-dependent mode of adhesion. Here, we used recombinant FimH variants with a weakened inter-domain interaction and show that a fast and sustained allosteric activation of FimH can also occur under static, non-shear conditions. Moreover, it appears that lectin domain conformational activation happens intrinsically at a constant rate, independently from its ability to interact with the pilin domain or mannose. However, the latter two factors control the rate of FimH deactivation. Thus, the allosteric catch bond mechanism can be a much broader phenomenon involved in both fast and strong cell-pathogen attachments under a broad range of hydrodynamic conditions. This concept that allostery can enable more effective receptor-ligand interactions is fundamentally different from the conventional wisdom that allostery provides a mechanism to turn binding off under specific conditions.  相似文献   

11.
    
After decades of progress in computational protein design, the design of proteins folding and functioning in lipid membranes appears today as the next frontier. Some notable successes in the de novo design of simplified model membrane protein systems have helped articulate fundamental principles of protein folding, architecture and interaction in the hydrophobic lipid environment. These principles are reviewed here, together with the computational methods and approaches that were used to identify them. We provide an overview of the methodological innovations in the generation of new protein structures and functions and in the development of membrane-specific energy functions. We highlight the opportunities offered by new machine learning approaches applied to protein design, and by new experimental characterization techniques applied to membrane proteins. Although membrane protein design is in its infancy, it appears more reachable than previously thought.  相似文献   

12.
    
Herein, the impact of the halloysite nanotubes to suppress the side effects of Asparaginase (ANase) cellular proliferation was investigated. Methods: A total of 100 adult male mice was employed. These mice were divided into four equal groups; Group 1 (control), Group 2 (ESC group) of a single dose of 0.15 ml Ehrlich cells (2 × 106) intraperitoneal infusion(IP), Group 3 (ESC + ANase group) received six doses equal treatments of Intratumoral (IT) 0.07 ml Aspragnase (7 mg/kg) over two weeks. For two weeks, Group 4 (ESC + ASNase + HNTs) received an IT administration of 0.07 ml Asparaginase stocked on Halloysite nanotubes (HNTs) (30 mg/kg) three times per week. A blood specimen was collected, and the liver was removed to be investigated histologically. Results: TEM measurements for the Halloysite nanoclay showed their tubular cylindrical shape with a mean diameter of 50 nm and an average length of 1 μm, whereas The X-ray diffraction pattern of the Halloysite nanoclay showed their characteristic peaks. ESC increases the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin than control and other groups, even as albumin and total protein were decreasing. After using Halloysite Nanotube, the rates of these variables were enhanced up to 75%. The hepatocytes histological studies showed protection against Ehrlich Solid carcinoma-induced degenerative, necrotic, and inflammatory changes up to 70%. In conclusion, halloysite nanotubes have demonstrated effective removal of Ehrlich solid carcinoma in mice using an ASNase delivery system. It promoted the ASNase to inhibit the adverse effect of ANase's on the liver and remove the tumour cells.  相似文献   

13.
    
Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.  相似文献   

14.
    
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15.
    
Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O-acyltransferase (GOAT) catalyzes this posttranslational modification, which is essential for ghrelin to bind and activate its cognate GHS-R1a receptor. Inhibition of GOAT offers a potential avenue for modulating ghrelin signaling for therapeutic effect. Defining the molecular characteristics of ghrelin that lead to binding and recognition by GOAT will facilitate the development and optimization of GOAT inhibitors. We show that small peptide mimics of ghrelin substituted with 2,3-diaminopropanoic acid in place of the serine at the site of octanoylation act as submicromolar inhibitors of GOAT. Using these chemically modified analogs of desacyl ghrelin, we define key functional groups within the N-terminal sequence of ghrelin essential for binding to GOAT and determine GOAT’s tolerance to backbone methylations and altered amino acid stereochemistry within ghrelin. Our study provides a structure-activity analysis of ghrelin binding to GOAT that expands upon activity-based investigations of ghrelin recognition and establishes a new class of potent substrate-mimetic GOAT inhibitors for further investigation and therapeutic interventions targeting ghrelin signaling.  相似文献   

16.
    
Indole is a versatile pharmacophore, a privileged scaffold and an outstanding heterocyclic compound with wide ranges of pharmacological activities due to different mechanisms of action. It is an superlative moiety in drug discovery with the sole property of resembling different structures of the protein. Plenty of research has been taking place in recent years to synthesize and explore the various therapeutic prospectives of this moiety. This review summarizes some of the recent effective chemical synthesis (2014–2018) for indole ring. This review also emphasized on the structure–activity relationship (SAR) to reveal the active pharmacophores of various indole analogues accountable for anticancer, anticonvulsant, antimicrobial, antitubercular, antimalarial, antiviral, antidiabetic and other miscellaneous activities which have been investigated in the last five years. The precise features with motives and framework of each research topic is introduced for helping the medicinal chemists to understand the perspective of the context in a better way. This review will definitely offer the platform for researchers to strategically design diverse novel indole derivatives having different promising pharmacological activities with reduced toxicity and side effects.  相似文献   

17.
    
Introduction and aimBlastocystis is a common enteric parasite, having a worldwide distribution. Many antimicrobial agents are effective against it, yet side effects and drug resistance have been reported. Thus, ongoing trials are being conducted for exploring anti-Blastocystis alternatives. Proteases are attractive anti-protozoal drug targets, having documented roles in Blastocystis. Serine proteases are present in both hepatitis C virus and Blastocystis. Since drug repositioning is quite trendy, the in vitro efficacy of simeprevir (SMV), an anti-hepatitis serine protease inhibitor, against Blastocystis was investigated in the current study.MethodsStool samples were collected from patients, Alexandria, Egypt. Concentrated stools were screened using direct smears, trichrome, and modified Ziehl-Neelsen stains to exclude parasitic co-infections. Positive stool isolates were cultivated, molecularly subtyped for assessing the efficacy of three SMV doses (100,150, and 200 μg/ml) along 72 hours (h), on the most common subtype, through monitoring parasite growth, viability, re-culture, and also via ultrastructure verification. The most efficient dose and duration were later tested on other subtypes.ResultsResults revealed that Blastocystis was detected in 54.17% of examined samples. Molecularly, ST3 predominated (62%), followed by ST1 (8.6%) and ST2 (3.4%). Ascending concentrations of SMV progressively inhibited growth, viability, and re-culture of treated Blastocystis, with a non-statistically significant difference when compared to the therapeutic control metronidazole (MTZ). The most efficient dose and duration against ST3 was 150 µg/ml for 72 h. This dose inhibited the growth of ST3, ST1, and ST2 with percentages of 95.19%, 94.83%, and 94.74%, successively and viability with percentages of 98.30%, 98.09%, and 97.96%, successively. This dose abolished Blastocystis upon re-culturing. Ultra-structurally, SMV induced rupture of Blastocystis cell membrane leading to necrotic death, versus the reported apoptotic death caused by MTZ. In conclusion, 150 µg/ml SMV for 72 h proved its efficacy against ST1, ST2, and ST3 Blastocystis, thus sparing the need for pre-treatment molecular subtyping in developing countries.  相似文献   

18.
    
Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-21 screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding.  相似文献   

19.
The aim of this research is to analyze the potential impact of the COVID-19 infection on the serum biochemical concentration of children 6 months after recovery from the infection.The study included 72 children with a median age of 11 years. The case group consisted of 37 children who had contracted COVID-19 6 months prior to the analysis. They reported no other pre- or post-covid chronic or systemic diseases. The control group consisted of 35 children who had no prior record of COVID-19 infection.The analysis showed a substantial variation (P = 0.026) in the mean urea values (mmol/L) between the case group (4.513 ± 0.839) and the control group (5.425 ± 1.173). However, both groups' urea levels were within the normal range of their age group. No statistical differences were found analyzing the variations between the two groups in the levels of LDH, AST, ALT, BiliT, GGT, AlbBCG2, CRP, CK, AlKP, UA, Phos, Crea2, Gluc, Ca, Na, K, Cl, TP, TC, TG, and HDL (P > 0.05). The DMFT score was substantially greater (P < 0.002) in the infected team (5.38 ± 2.841) in comparison to the non-infected group (2.6 ± 2.257).The study indicates that COVID-19 infection does not leave biochemical alterations among children who did not have pre-existing conditions. The biochemical analysis suggests that children recover better than adults from COVID-19. Furthermore, it calls for investigating non-lethal COVID-19 infection as a tool to discover underlying conditions. The DMFT score shows a correlation between COVID-19 infection and caries. However, the nature of the correlation is yet to be investigated.  相似文献   

20.
    
The purpose of this work was to investigate the protective effect of five essential oils (EOs); Rosmarinus officinalis, Thymus vulgaris, Origanum compactum Benth., Eucalyptus globulus Labill. and Ocimum basilicum L.; against oxidative stress induced by hydrogen peroxide in Saccharomyces cerevisiae. The chemical composition of the EOs was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The in vitro antioxidant activity was evaluated and the protective effect of EOs was investigated. Yeast cells were pretreated with different concentrations of EOs (6.25–25 µg/ml) for an hour then incubated with H2O2 (2 mM) for an additional hour. Cell viability, antioxidants (Catalase, Superoxide dismutase and Glutathione reductase) and metabolic (Succinate dehydrogenase) enzymes, as well as the level of lipid peroxidation (LPO) and protein carbonyl content (PCO) were evaluated. The chemical composition of EOs has shown the difference qualitatively and quantitatively. Indeed, O. compactum mainly contained Carvacrol, O. basilicum was mainly composed of Linalool, T. vulgaris was rich in thymol, R. officinalis had high α-Pinene amount and for E. globulus, eucalyptol was the major compound. The EOs of basil, oregano and thyme were found to possess the highest amount of total phenolic compounds. Moreover, they have shown the best protective effect on yeast cells against oxidative stress induced by H2O2. In addition, in a dose dependent manner of EOs in yeast medium, treated cells had lower levels of LPO, lower antioxidant and metabolic enzymes activity than cells exposed to H2O2 only. The cell viability was also improved. It seems that the studied EOs are efficient natural antioxidants, which can be exploited to protect against damages and serious diseases related to oxidative stress.  相似文献   

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