2,204 results match your criteria pharmacologically relevant


Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies.

J Immunother Cancer 2021 Jul;9(7)

Roche Pharma Research and Early Development, Roche Innovation Centre Zurich, Schlieren, Switzerland.

Background: T cell engagers are bispecific antibodies recognizing, with one moiety, the CD3ε chain of the T cell receptor and, with the other moiety, specific tumor surface antigens. Crosslinking of CD3 upon simultaneous binding to tumor antigens triggers T cell activation, proliferation and cytokine release, leading to tumor cell killing. Treatment with T cell engagers can be associated with safety liabilities due to on-target on-tumor, on-target off-tumor cytotoxic activity and cytokine release syndrome (CRS). Read More

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Drug Metab Dispos 2021 Jul 29. Epub 2021 Jul 29.

Pharmaceutics, University of Washington, United States

(-)-Δ-tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. In humans, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and non-psychoactive circulating metabolites of THC, respectively. Whether these cannabinoids are substrates or inhibitors of human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) is unknown. Read More

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Electronic nicotine vapor exposure produces differential changes in central amygdala neuronal activity, thermoregulation and locomotor behavior in male mice.

eNeuro 2021 Jul 28. Epub 2021 Jul 28.

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Nicotine is an addictive substance historically consumed through smoking and more recently through the use of electronic vapor devices. The increasing prevalence and popularity of vaping prompts the need for preclinical rodent models of nicotine vapor exposure and an improved understanding of the impact of vaping on specific brain regions, bodily functions, and behaviors. We used a rodent model of electronic nicotine vapor exposure to examine the cellular and behavioral consequences of acute and repeated vapor exposure. Read More

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Perturbations in dynamical models of whole-brain activity dissociate between the level and stability of consciousness.

PLoS Comput Biol 2021 Jul 27;17(7):e1009139. Epub 2021 Jul 27.

Department of Physics, University of Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria-Buenos Aires, Argentina.

Consciousness transiently fades away during deep sleep, more stably under anesthesia, and sometimes permanently due to brain injury. The development of an index to quantify the level of consciousness across these different states is regarded as a key problem both in basic and clinical neuroscience. We argue that this problem is ill-defined since such an index would not exhaust all the relevant information about a given state of consciousness. Read More

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Comparing Tumor Cell Invasion and Myeloid Cell Composition in Compatible Primary and Relapsing Glioblastoma.

Cancers (Basel) 2021 Jul 20;13(14). Epub 2021 Jul 20.

Neurosurgical Research, University Hospital Ludwig Maximilian University Munich, 81377 Munich, Germany.

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. Read More

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Recent Advances on Photoinduced Cascade Strategies for the Synthesis of N-Heterocycles.

Chem Rec 2021 Jul 21. Epub 2021 Jul 21.

Department of Chemistry, Federal University of São Carlos, Rodovia Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, Brazil -, 13565-905.

Over the last decade, visible-light photocatalysis has proved to be a powerful tool for the construction of N-heterocyclic frameworks, important constituents of natural products, insecticides, pharmacologically relevant therapeutic agents and catalysts. This account highlights recent developments and established methods towards the photocatalytic cascades for preparation of different classes of N-heterocycles, giving emphasis on our contribution to the field. Read More

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Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects.

Cell Death Dis 2021 Jul 16;12(8):713. Epub 2021 Jul 16.

Centre de Recherche des Cordeliers, INSERM UMRS1138, Université de Paris, Sorbonne Université, Team "Metabolism, Cancer & Immunity", 75006, Paris, France.

Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Read More

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Statins: Neurobiological underpinnings and mechanisms in mood disorders.

Neurosci Biobehav Rev 2021 09 13;128:693-708. Epub 2021 Jul 13.

Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, VIC, Australia; Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia; Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia. Electronic address:

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Read More

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September 2021

Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol's Action on Mesolimbic Dopamine.

Front Neurosci 2021 28;15:675061. Epub 2021 Jun 28.

Center of Excellence for the Study of Neurobiology of Addiction, University of Cagliari, Cagliari, Italy.

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks' addictive liability, causes millions of deaths yearly. Ethanol's addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. Read More

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How much can medical management alone improve the outcome of adult drug-resistant epilepsy? An exploratory study on possibilities and limitations of combining multiple therapeutic actions.

Authors:
Ruggero Serafini

Epilepsy Behav 2021 Jul 6;122:108065. Epub 2021 Jul 6.

Department of Neurology, University of Utah Clinical Neuroscience Center, George E. Wahlen VA Medical Center, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA. Electronic address:

Purpose: Failure to control epileptic seizures with two medications, adequately chosen and dosed, indicates drug-resistant epilepsy (DRE). The chance of pharmacologically controlling seizures is low for patients with DRE and uncontrolled seizures who are not candidates for surgery, who have already undergone surgery, or who already had a vagus nerve stimulator (VNS) placed. Patients experiencing these conditions must instead rely on medical management of their seizures, and there is no breakthrough solution on the horizon. Read More

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Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease.

Mol Pharm 2021 Aug 9;18(8):2906-2923. Epub 2021 Jul 9.

School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, PR China.

Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short half-life. Read More

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Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer.

Biomolecules 2021 Jun 30;11(7). Epub 2021 Jun 30.

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. Read More

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Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells.

Int J Mol Sci 2021 Jun 22;22(13). Epub 2021 Jun 22.

Departments of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Read More

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Role and Perspective of Molecular Simulation-Based Investigation of RNA-Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding.

Molecules 2021 Jun 3;26(11). Epub 2021 Jun 3.

Institute for Advanced Simulation (IAS-5), Forschungszentrum Jülich, 52425 Jülich, Germany.

Aberrant RNA-protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Read More

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Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study.

Pulm Ther 2021 Jun 26. Epub 2021 Jun 26.

Department of Clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.

Introduction: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0. Read More

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Oxindole and its derivatives: A review on recent progress in biological activities.

Biomed Pharmacother 2021 Jun 23;141:111842. Epub 2021 Jun 23.

Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India. Electronic address:

Oxindole has been shown to be a pharmacologically advantageous scaffold having many biological properties that are relevant to medicinal chemistry. The simplicity and widespread occurrence of this scaffold in plant-based alkaloids have further reinforced oxindole's merit in the domain of novel drug discovery. First extracted from Uncaria tomentosa, commonly the known as cat claw's plant which was found abundantly in the Amazon rainforest, molecules with the oxindole moiety have been shown to be common in a wide variety of compounds extracted from plant sources. Read More

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A nonhuman primate model of blue light-induced progressive outer retina degeneration showing brimonidine drug delivery system-mediated cyto- and neuroprotection.

Exp Eye Res 2021 Jun 19;209:108678. Epub 2021 Jun 19.

Allergan (an AbbVie company), 2525 Dupont Drive, Irvine, CA, 92612, USA. Electronic address:

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by atrophy of the retinal pigment epithelium (RPE), loss of photoreceptors, and disruption of choriocapillaris. Excessive light exposure is toxic to the retina and is a known risk factor for AMD. We first investigated the effects of blue light-induced phototoxicity on RPE and photoreceptors in nonhuman primates (NHPs, a model of progressive retinal degeneration) and then evaluated the potential cyto- and neuroprotective effects of the brimonidine drug delivery system (Brimo DDS). Read More

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Medicinal Plants and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Treatment of Arthritis: A Literature Review.

Altern Ther Health Med 2021 Jun 18. Epub 2021 Jun 18.

Context: Arthritis is an inflammatory disease of diarthrodial joints and is associated with swollen inflamed joints, disruption of joints, and loss of integrity of articular cartilage and synovial joints.

Objective: The current review intended to examine the data on the epidemiology, causes, clinical diagnosis, and prevention and control of different types of arthritis and on the use of medicinal plants in gouty arthritis.

Design: The research team performed a literature review, searching relevant literature databases, including bioRxiv, medRxiv, Google Scholar, Embase, PsychINFO, and PubMed. Read More

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Acute cell stress screen with supervised machine learning predicts cytotoxicity of excipients.

J Pharmacol Toxicol Methods 2021 Jun 15:107088. Epub 2021 Jun 15.

Preclinical Safety, Translational Medicine, Novartis Institutes of Biomedical Research, Cambridge, MA, 02139, USA. Electronic address:

Excipients serve as vehicles, preservatives, solubilizers, and colorants for drugs, food, and cosmetics. They are considered to be inert at biological targets; however, several reports suggest that some could interact with human targets and cause unwanted effects. We investigated 40 commonly used drug excipients for cellular stress in the AsedaSciences® SYSTEMETRIC® Cell Health Screen, which was developed to estimate toxicity risk of small molecular entities (SMEs). Read More

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Polymeric micelle mediated follicular delivery of spironolactone: Targeting the mineralocorticoid receptor to prevent glucocorticoid-induced activation and delayed cutaneous wound healing.

Int J Pharm 2021 Jul 4;604:120773. Epub 2021 Jun 4.

School of Pharmaceutical Sciences, University of Geneva, CMU - 1 rue Michel Servet, 1211 Geneva 4, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU - 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Electronic address:

Impaired wound healing in patients receiving glucocorticoid therapy is a serious clinical concern: mineralocorticoid receptor (MR) antagonists can counter glucocorticoid-induced off-target activation of MR receptors. The aim of this study was to investigate the cutaneous delivery of the potent MR antagonist, spironolactone (SPL), from polymeric micelle nanocarriers, prepared using a biodegradable copolymer, methoxy-poly(ethylene glycol)-di-hexyl-substituted-poly(lactic acid). Immunofluorescent labelling of the MR showed that it was principally located in the pilosebaceous unit (PSU), justifying the study rationale since polymeric micelles accumulate preferentially in appendageal structures. Read More

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Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits.

Pharmaceuticals (Basel) 2021 May 18;14(5). Epub 2021 May 18.

Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. Read More

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Marine Anthraquinones: Pharmacological and Toxicological Issues.

Mar Drugs 2021 May 13;19(5). Epub 2021 May 13.

Department for Life Quality Studies, Alma Mater Studiorum, Università di Bologna, Corso d'Augusto 237, 47921 Rimini, Italy.

The marine ecosystem, populated by a myriad of animals, plants, and microorganisms, is an inexhaustible reservoir of pharmacologically active molecules. Among the multiple secondary metabolites produced by marine sources, there are anthraquinones and their derivatives. Besides being mainly known to be produced by terrestrial species, even marine organisms and the uncountable kingdom of marine microorganisms biosynthesize anthraquinones. Read More

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Seasonal Variations of Rosmarinic Acid and Its Glucoside and Expression of Genes Related to Their Biosynthesis in Two Medicinal and Aromatic Species of subg. .

Biology (Basel) 2021 May 22;10(6). Epub 2021 May 22.

Department of Pharmaceutical Biology and Biotechnology, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.

Kar. and B.T. Read More

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Ligand-Dependent Conformational Transitions in Molecular Dynamics Trajectories of GPCRs Revealed by a New Machine Learning Rare Event Detection Protocol.

Molecules 2021 May 20;26(10). Epub 2021 May 20.

Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.

Central among the tools and approaches used for ligand discovery and design are Molecular Dynamics (MD) simulations, which follow the dynamic changes in molecular structure in response to the environmental condition, interactions with other proteins, and the effects of ligand binding. The need for, and successes of, MD simulations in providing this type of essential information are well documented, but so are the challenges presented by the size of the resulting datasets encoding the desired information. The difficulty of extracting information on mechanistically important state-to-state transitions in response to ligand binding and other interactions is compounded by these being rare events in the MD trajectories of complex molecular machines, such as G-protein-coupled receptors (GPCRs). Read More

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Anemarrhena saponins attenuate insulin resistance in rats with high-fat diet-induced obesity via the IRS-1/PI3K/AKT pathway.

J Ethnopharmacol 2021 Sep 27;277:114251. Epub 2021 May 27.

Department of Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address:

Ethnopharmacological Relevance: Anemarrhena asphodeloides is the dry rhizome of Anemarrhena asphodeloides Bge. Anemarrhena Saponins isolated from Anemarrhena asphodeloides are one of the pharmacologically active components of this plant and have blood lipid reduction and blood glucose reduction properties. These facts suggest that these saponins might be helpful in the treatment of insulin resistance. Read More

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September 2021

Novel polyester-based thermoplastic elastomers for 3D-printed long-acting drug delivery applications.

J Control Release 2021 Jul 24;335:290-305. Epub 2021 May 24.

Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria. Electronic address:

To improve patient compliance and personalised drug delivery, long-acting drug delivery devices (LADDDs), such as implants and inserts, greatly benefit from a customisation in their shape through the emerging 3D-printing technology, since their production usually follows a one-size-fits-most approach. The use of 3D-printing for LADDDs, however, is mainly limited by the shortage of flawlessly 3D-printable, yet biocompatible materials. The present study tackles this issue by introducing a novel, non-biodegradable material, namely a polyester-based thermoplastic elastomer (TPC) - a multi-block copolymer containing alternating semi-crystalline polybutylene terephthalate hard segments and poly-ether-terephthalate amorphous soft segments. Read More

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Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL-AF4 fusion protein.

Sci Rep 2021 May 25;11(1):10883. Epub 2021 May 25.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, PRB, 720 S. Donahue Dr., Auburn, AL, 36849, USA.

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Read More

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Liver toxicity observed with lorlatinib when combined with strong CYP3A inducers: evaluation of cynomolgus monkey as a nonclinical model for assessing the mechanism of combinational toxicity.

Toxicol Sci 2021 May 21. Epub 2021 May 21.

Drug Safety Research and Development, Pfizer Inc, San Diego, CA, 92121.

Lorlatinib is a potent small molecule anaplastic lymphoma kinase inhibitor approved for the treatment of patients with non-small cell lung cancer. In a drug-drug-interaction study in healthy human participants, liver enzyme elevations were observed when a single 100 mg dose of lorlatinib was administered after multiple doses of rifampin, a strong cytochrome P450 (CYP) 3 A inducer and a pregnane X receptor (PXR) agonist. A series of in vitro and in vivo studies were conducted to evaluate potential mechanisms for the observed clinical toxicity. Read More

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Modeling SARS-CoV-2 and Influenza Infections and Antiviral Treatments in Human Lung Epithelial Tissue Equivalents.

bioRxiv 2021 May 12. Epub 2021 May 12.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third coronavirus in less than 20 years to spillover from an animal reservoir and cause severe disease in humans. High impact respiratory viruses such as pathogenic beta-coronaviruses and influenza viruses, as well as other emerging respiratory viruses, pose an ongoing global health threat to humans. There is a critical need for physiologically relevant, robust and ready to use, cellular assay platforms to rapidly model the infectivity of emerging respiratory viruses and discover and develop new antiviral treatments. Read More

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Cork-in-bottle mechanism of inhibitor binding to mammalian complex I.

Sci Adv 2021 May 14;7(20). Epub 2021 May 14.

MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.

Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3. Read More

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