Breast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER-) breast cancer and triple-negative breast cancer ...(TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.
Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify ligands for biological targets given that it enables the target to direct the synthesis and amplification of its ...strongest binder(s) from the library of interconverting compounds. Since the first report of DCC applied to the discovery of binders for a protein, this elegant tool has been employed on a range of protein targets at various stages of medicinal-chemistry projects. A series of suitable, reversible reactions that are biocompatible have been established and the portfolio of analytical techniques is growing. Despite progress, in most cases, the libraries employed remain of moderate size. We present here the most recent advances in the field of DCC applied to protein targets, paying particular attention to the experimental conditions and analytical methods chosen.
Dynamic combinatorial chemistry enables efficient identification of protein binder(s) from a library of interconverting compounds. The library responds to the addition of the target by amplifying the strongest binder.
There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost ...most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens
. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.
The molecular nanoscale organization of the surfaceome is a fundamental regulator of cellular signaling in health and disease. Technologies for mapping the spatial relationships of cell surface ...receptors and their extracellular signaling synapses would unlock theranostic opportunities to target protein communities and the possibility to engineer extracellular signaling. Here, we develop an optoproteomic technology termed LUX-MS that enables the targeted elucidation of acute protein interactions on and in between living cells using light-controlled singlet oxygen generators (SOG). By using SOG-coupled antibodies, small molecule drugs, biologics and intact viral particles, we demonstrate the ability of LUX-MS to decode ligand receptor interactions across organisms and to discover surfaceome receptor nanoscale organization with direct implications for drug action. Furthermore, by coupling SOG to antigens we achieved light-controlled molecular mapping of intercellular signaling within functional immune synapses between antigen-presenting cells and CD8
T cells providing insights into T cell activation with spatiotemporal specificity. LUX-MS based decoding of surfaceome signaling architectures thereby provides a molecular framework for the rational development of theranostic strategies.
The COVID-19 pandemic represents an unprecedented challenge for the researchers to offer safe, tolerable, and effective treatment strategies for its causative agent known as SARS-CoV-2. With the ...rapid evolution of the pandemic, even the off-label use of existing drugs has been restricted by limited availability. Several old antivirals, antimalarial, and biological drugs are being reconsidered as possible therapies. The effectiveness of the controversial treatment options for COVID-19 such as nonsteroidal antiinflammatory drugs, angiotensin 2 conversion enzyme inhibitors and selective angiotensin receptor blockers was also discussed. A systemic search in the PubMed, Science Direct, LitCovid, Chinese Clinical Trial Registry, and ClinicalTrials.gov data bases was conducted using the keywords “coronavirus drug therapy,” passive immunotherapy for COVID-19’, “convalescent plasma therapy,” (CPT) “drugs for COVID-19 treatment,” “SARS-CoV-2,” “COVID-19,” “2019-nCoV,” “coronavirus immunology,” “microbiology,” “virology,” and individual drug names. Systematic reviews, case presentations and very recent clinical guidelines were included. This narrative review summarizes the available information on possible therapies for COVID-19, providing recent data to health professionals.
Ginkgolide A is a highly active platelet activating factor antagonist cage molecule which was isolated from the leaves of the Ginkgo biloba L. It is known for its inflammatory and immunological ...potentials. This review aims to sketch a current scenario on its therapeutic activities on the basis of scientific reports in the databases. A total 30 articles included in this review suggests that ginkgolide A has many important biological activities, including anti-inflammatory, anticancer, anxiolytic-like, anti-atherosclerosis and anti-atherombosis, neuro- and hepatoprotective effects. There is a lack of its toxicological (e.g. toxicity, cytotoxicity, genotoxicity and mutagenitcity) profile. In conclusion, ginkgolide A may be one of the potential therapeutic lead compounds, especially for the treatment of cardiovascular, hepatological, and neurological diseases and disorders. More studies are necessary on this hopeful therapeutic agent.
Nerol, a monoterpene is evident to possess diverse biological activities, including antioxidant, anti-microbial, anti-spasmodic, anthelmintic, and anti-arrhythmias. This study aims to evaluate its ...hepatoprotective effect against paracetamol-induced liver toxicity in a rat model. Five groups of rats (n = 7) were orally treated (once daily) with 0.05% tween 80 dissolved in 0.9% NaCl solution (vehicle), paracetamol 640 mg/kg (negative control), 50 mg/kg silymarin (positive control), or nerol (50 and 100 mg/kg) for 14 days, followed by the hepatotoxicity induction using paracetamol (PCM). The blood samples and livers of the animals were collected and subjected to biochemical and microscopical analysis. The histological findings suggest that paracetamol caused lymphocyte infiltration and marked necrosis, whereas maintenance of the normal hepatic structural was observed in group pre-treated with silymarin and nerol. The rats pre-treated with nerol significantly and dose-dependently reduced the hepatotoxic markers in animals. Nerol at 100 mg/kg significantly reversed the paracetamol-induced altered situations, including the liver enzymes, plasma proteins, antioxidant enzymes and serum bilirubin, lipid peroxidation (LPO) and cholesterol e.g., total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) levels in animals. Taken together, nerol exerted significant hepatoprotective activity in rats in a dose-dependent manner. PCM-induced toxicity and nerol induced hepatoprotective effects based on expression of inflammatory and apoptosis factors will be future line of work for establishing the precise mechanism of action of nerol in Wistar albino rats.
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•Nerol exerts significant hepatoprotective effects in rats in a dose-dependent manner.•Administration of nerol significant reduces ALT and AST enzymes levels in blood.•Nerol can significantly reverse the paracetamol-induced impaired liver conditions.
The mammalian membrane‐bound O‐acyltransferase (MBOAT) superfamily is involved in biological processes including growth, development and appetite sensing. MBOATs are attractive drug targets in cancer ...and obesity; however, information on the binding site and molecular mechanisms underlying small‐molecule inhibition is elusive. This study reports rational development of a photochemical probe to interrogate a novel small‐molecule inhibitor binding site in the human MBOAT Hedgehog acyltransferase (HHAT). Structure‐activity relationship investigation identified single enantiomer IMP‐1575, the most potent HHAT inhibitor reported to‐date, and guided design of photocrosslinking probes that maintained HHAT‐inhibitory potency. Photocrosslinking and proteomic sequencing of HHAT delivered identification of the first small‐molecule binding site in a mammalian MBOAT. Topology and homology data suggested a potential mechanism for HHAT inhibition which was confirmed by kinetic analysis. Our results provide an optimal HHAT tool inhibitor IMP‐1575 (Ki=38 nM) and a strategy for mapping small molecule interaction sites in MBOATs.
Structure‐activity relationship analysis of Hedgehog acyltransferase (HHAT) inhibitors allowed rational design of photochemical probes for HHAT. Probe photocrosslinking identified the first small‐molecule inhibitor binding site in HHAT and revealed the inhibitory mechanism, providing an optimal HHAT tool inhibitor IMP‐1575 (Ki=38 nM) for future studies.
Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating ...sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis.
The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds
SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5.
Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.
Carbon-tetrachloride (CCl4) is well-known to cause liver damage due to severe oxidative stress. Nerol, on the other hand, is a monoterpene that is antioxidant, antiviral, antibacterial, ...anti-inflammatory, and anxiolytic. This study set out to determine if nerol may be used as a prophylactic measure against the oxidative stress mediated hepatic injury caused by CCl4.
For the aim of this experiment, 35 male Sprague-Dawley rats ranging in body weight (BW) from 140 to 180 g were split into five separate groups. With the exception of vehicle control group 1, all experimental rats were subjected to carbon tetrachloride exposure through intra-peritoneal injection at a 0.7 mL/kg body weight dose once a week for 4 weeks (28 days). The treatment groups 3 and 4 received oral administration of nerol at 50 and 100 mg/kg BW for 28 days. In the same time period, the standard control group received 100 mg/kg BW silymarin.
Serum hepatic markers, lipid profiles, albumin, globulin, bilirubin, and total protein were all substantially improved in nerol-treated rats in a dose-dependent manner that had been exposed to CCl4 compared to the only CCl4-treated group. Carbon tetrachloride-exposed rats had lower glutathione, superoxide dismutase, and catalase levels and higher thio-barbituric acid reactive substances (TBARS) levels than normal rats. In contrast, administration of nerol shown a significant augmentation in the concentrations of these antioxidant compounds, while concurrently inducing a decline in the levels of TBARS in the hepatic tissue. In a similar vein, the histo-pathological examination yielded further evidence indicating that nerol offered protection to the hepatocyte against damage generated by CCl4.
According to the findings of our investigation, nerol has potential as a functional element to shield the liver from harm brought on by ROS that are caused by CCL4.
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