Articles de revues : « Sar/spr »

1

Dudek, F. Edward. « Selective Inhibitory Interneuron Loss Produces Chronic Hippocampal Hyperexcitability ». Epilepsy Currents 2, n^o 1 (janvier 2002) : 21–22. http://dx.doi.org/10.1111/j.1535-7597.2002.00007.x.

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Focal Inhibitory Interneuron Loss and Principal Cell Hyperexcitability in the Rat Hippocampus After Microinjection of a Neurotoxic Conjugate of Saporin and a Peptidase-Resistant Analog of Substance P Martin JL, Sloviter RS J Comp Neurol 2001;436:127–152 Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, so-matostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2)-positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase—immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)—and beta-synu-clein—LI, as well as by Timm staining, all of which revealed relatively normal patterns of excitatory terminal distribution. Control injections produced minor damage at the injection site, but no apparent specific loss of SPR-LI. One to 12 weeks after injection of SSP-saporin, extracellular electrophysiological field responses recorded in the CA1 pyramidal and dentate granule cell layers in response to afferent stimulation were blindly evaluated simultaneously in two sites 1–2 mm apart along the longitudinal hippocampal axis. SSP-saporin-treated rats exhibited relatively normal responses in some sites, whereas disinhibition and hyperexcitability indistinguishable from the pathophysiology produced by experimental status epilepticus were simultaneously recorded at adjacent sites. Anatomic analysis of the recording sites in each animal revealed that epileptiform pathophysiology was consistently observed only within areas of SPR ablation, whereas relatively normal evoked responses were recorded from immediately adjacent and relatively unaffected regions. These data establish the efficacy of [Sar(9), Met(O(2))(11)] Substance P-saporin for producing a selective and spatially extensive ablation of hippocampal inhibitory interneurons in vivo and a highly focal disinhibition that was restricted to the site of interneuron loss. These results also demonstrate that the “epileptic” pathophysiology produced by experimental status epilepticus or head trauma can be replicated by focal interneuron loss per se, without involving principal cell loss and other interpretive confounds inherent in the use of global neurologic injury models.

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Rice, Amy J., Russell P. Pesavento, Jinhong Ren, Isoo Youn, Youngjin Kwon, Kassapa Ellepola, Chun-Tao Che, Michael E. Johnson et Hyun Lee. « Identification of Small Molecule Inhibitors against Staphylococcus aureus Dihydroorotase via HTS ». International Journal of Molecular Sciences 22, n^o 18 (15 septembre 2021) : 9984. http://dx.doi.org/10.3390/ijms22189984.

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Drug-resistant Staphylococcus aureus is an imminent threat to public health, increasing the importance of drug discovery utilizing unexplored bacterial pathways and enzyme targets. De novo pyrimidine biosynthesis is a specialized, highly conserved pathway implicated in both the survival and virulence of several clinically relevant pathogens. Class I dihydroorotase (DHOase) is a separate and distinct enzyme present in gram positive bacteria (i.e., S. aureus, B. anthracis) that converts carbamoyl-aspartate (Ca-asp) to dihydroorotate (DHO)—an integral step in the de novo pyrimidine biosynthesis pathway. This study sets forth a high-throughput screening (HTS) of 3000 fragment compounds by a colorimetry-based enzymatic assay as a primary screen, identifying small molecule inhibitors of S. aureus DHOase (SaDHOase), followed by hit validation with a direct binding analysis using surface plasmon resonance (SPR). Competition SPR studies of six hit compounds and eight additional analogs with the substrate Ca-asp determined the best compound to be a competitive inhibitor with a KD value of 11 µM, which is 10-fold tighter than Ca-asp. Preliminary structure–activity relationship (SAR) provides the foundation for further structure-based antimicrobial inhibitor design against S. aureus.

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Huang, Johnny X., Mohammad A. K. Azad, Elizabeth Yuriev, Mark A. Baker, Roger L. Nation, Jian Li, Matthew A. Cooper et Tony Velkov. « Molecular Characterization of Lipopolysaccharide Binding to Humanα-1-Acid Glycoprotein ». Journal of Lipids 2012 (2012) : 1–15. http://dx.doi.org/10.1155/2012/475153.

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The ability of AGP to bind circulating lipopolysaccharide (LPS) in plasma is believed to help reduce the proinflammatory effect of bacterial lipid A molecules. Here, for the first time we have characterized human AGP binding characteristics of the LPS from a number of pathogenic Gram-negative bacteria:Escherichia coli,Salmonella typhimurium,Klebsiella pneumonia,Pseudomonas aeruginosa, andSerratia marcescens. The binding affinity and structure activity relationships (SAR) of the AGP-LPS interactions were characterized by surface plasma resonance (SPR). In order to dissect the contribution of the lipid A, core oligosaccharide andO-antigen polysaccharide components of LPS, the AGP binding affinity of LPS from smooth strains, were compared to lipid A, Kdo2-lipid A,Ra,Rd, andRerough LPS mutants. The SAR analysis enabled by the binding data suggested that, in addition to the important role played by the lipid A and core components of LPS, it is predominately the unique species- and strain-specific carbohydrate structure of theO-antigen polysaccharide that largely determines the binding affinity for AGP. Together, these data are consistent with the role of AGP in the binding and transport of LPS in plasma during acute-phase inflammatory responses to invading Gram-negative bacteria.

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Freidel, Matthew R., Pratiti A. Vakhariya, Shalinder K. Sardarni et Roger S. Armen. « The Dual-Targeted Fusion Inhibitor Clofazimine Binds to the S2 Segment of the SARS-CoV-2 Spike Protein ». Viruses 16, n^o 4 (20 avril 2024) : 640. http://dx.doi.org/10.3390/v16040640.

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Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results related to molecular docking and modeling of the structure–activity relationship (SAR) of a newly reported series of Clofazimine derivatives support the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure–sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronaviruses such as SARS-CoV, MERS, hCoV-229E, and hCoV-OC43.

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García Marín, Javier. « Deciphering the inhibition mechanism of a pseudokinase : integrin-bound kinase and cpd22 ». Anales de la Real Academia Nacional de Farmacia 88, n^o 88(02) (30 juin 2022) : 131–48. http://dx.doi.org/10.53519/analesranf.2022.88.02.03.

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According to World Health Organization (WHO) cancer is one of top non- infectious death causes worldwide. In this context, as such the searching of new potent and safe anticancer drugs is a hot point for pharmacy industry and academic investigation. Despite protein kinases have been one of the most explored anticancer targets, its evolutionary degenerated parents, pseudokinases, have attracted the attention of scientific community during the last decade. Integrin Linked Kinase (ILK) is a member of the human pseudokinome that has been claimed and validated as a prommissing target for neoplastic diseases. The only well-known ILK inhibitor, CPD22, has probed its activity in phenotypic assays, however very few knowledge regarding its mechanism of action at molecular level is available. Using chemoinformatic and molecular modelling techniques we were able to elucidate if this molecule is able to bind to ILK and how. Additionally, our model explains the SAR raised from the optimization campaign, and SPR experiments have probed, by first time, that this molecule binds to ILK, thus supporting the hypothesis of inhibition by direct binding and the computational model as well.

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Sizochenko, Natalia, et Jerzy Leszczynski. « Review of Current and Emerging Approaches for Quantitative Nanostructure-Activity Relationship Modeling ». Journal of Nanotoxicology and Nanomedicine 1, n^o 1 (janvier 2016) : 1–16. http://dx.doi.org/10.4018/jnn.2016010101.

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Quantitative structure-activity/property relationships (QSAR/QSPR) approaches that have been applied with success in a number of studies are currently used as indispensable tools in the computational analysis of nanomaterials. Evolution of nano-QSAR methodology to the ranks of novel field of knowledge has resulted in the development of new so-called “nano-descriptors” and extension of the statistical approaches domain. This brief review focuses on the critical analysis of advantages and disadvantages of existing methods of nanoparticles' representation and their analysis in framework of structure-activity relationships. It summarizes recent QSAR/QSPR studies on inorganic nanomaterials. Here the authors describe practices for the QSAR modeling of inorganic nanoparticles, existing datasets, and discuss applicable descriptors and future perspectives of this field. About 50 different (Q)SAR/SPR models for inorganic nanomaterials have been developed during the past 5 years. An analysis of these peer reviewed publications shows that the most popular property of nanoparticles modeled via QSAR is their toxicity towards different bacteria, cell lines, and microorganisms. It has been clearly shown how nano-QSAR can contribute to the elucidation of toxicity mechanisms and different physical properties of inorganic nanomaterials.

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Gerner, Ingrid, Gabriele Graetschel, Jürgen Kahl et Eva Schlede. « Development of a Decision Support System for the Introduction of Alternative Methods into Local Irritancy/Corrosivity Testing Strategies. Development of a Relational Database ». Alternatives to Laboratory Animals 28, n^o 1 (janvier 2000) : 11–28. http://dx.doi.org/10.1177/026119290002800106.

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For new chemical substances that are notified within the European Union, data sets have to be submitted to the National Competent Authorities. The data submitted have to demonstrate the physicochemical and toxic properties of the new chemical, such as solubility, partition coefficients and spectra, as well as acute toxic properties and the potential to cause local irritant or corrosive effects. In order to minimise testing for notification purposes (for example, animal testing), it is necessary to develop stepwise assessment procedures, including structure-activity considerations, alternative methods (for example, in vitro tests), and computerised structure-activity relationship (SAR) models. An electronic database was developed which contains physicochemical and toxicological data on approximately 1300 chemical substances. It is used for regulatory structure-property relationship (SPR) and SAR considerations, and for the development of rules for a decision support system (DSS) for the introduction of alternative methods into local irritancy/corrosivity testing strategies. The information stored in the database is derived from proprietary data, so it is not possible to publish the data directly. Therefore, the database is evaluated by regulators, and the information derived from the data is used for the development of scientific information about SARs. This information can be published, for example, by means of tables correlating measured physicochemical values and specific toxic effects caused by the measured chemical. This information is introduced to the public by means of a DSS that predicts local irritant/corrosive potential of a chemical by listing so-called exception rules of the kind IF (physicochemical property) A THEN not (toxic) Effect B and so-called structural rules of the kind IF Substructure A THEN Effect B. These DSS rules “translate” proprietary data into scientific knowledge that can be published.

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Scala, Maria Carmina, Mariangela Agamennone, Agostina Pietrantoni, Veronica Di Sarno, Alessia Bertamino, Fabiana Superti, Pietro Campiglia et Marina Sala. « Discovery of a Novel Tetrapeptide against Influenza A Virus : Rational Design, Synthesis, Bioactivity Evaluation and Computational Studies ». Pharmaceuticals 14, n^o 10 (23 septembre 2021) : 959. http://dx.doi.org/10.3390/ph14100959.

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Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase in virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. deeply investigated the mechanism of the anti-influenza virus effect of bovine lactoferrin (bLf) and the role of its tryptic fragments (the N- and C-lobes) in antiviral activity. Recently, through a truncation library, we identified the tetrapeptides, Ac-SKHS-NH2 (1) and Ac-SLDC-NH2 (2), derived from bLf C-lobe fragment 418–429, which were able to bind hemagglutinin (HA) and inhibit cell infection in a concentration range of femto- to picomolar. Starting from these results, in this work, we initiated a systematic SAR study on the peptides mentioned above, through an alanine scanning approach. We carried out binding affinity measurements by microscale thermophoresis (MST) and surface plasmon resonance (SPR), as well as hemagglutination inhibition (HI) and virus neutralization (NT) assays on synthesized peptides. Computational studies were performed to identify possible ligand–HA interactions. Results obtained led to the identification of an interesting peptide endowed with broad anti-influenza activity and able to inhibit viral infection to a greater extent of reference peptide.

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Ji, Xingyue. « Prodrug Strategies for Critical Drug Developability Issues : Part I ». Current Topics in Medicinal Chemistry 21, n^o 24 (septembre 2021) : 2155–56. http://dx.doi.org/10.2174/156802662124211104100228.

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Drug development is a very time, capital, and labor-intensive process. It was anticipated that bringing a novel chemical entity to market would take over a billion dollars and around 14 years [1]. In addition, drug development is characterized by a very high attrition rate both in preclinical and clinical studies. It was reported that only 40% of drug candidates with the most drug-like properties could make their way into clinical trials, and only 10% of these can eventually reach FDA approval [2]. After analyzing the data from seven UK‐based pharmaceutical companies from 1964 through 1985, Prentis et al. found that 39% of failure was attributed to poor pharmacokinetic (PK) profiles in humans, 29% was attributed to a lack of clinical efficacy, 21% was attributed to toxicity and adverse effects, and about 6% was attributed to commercial limitations [3]. When a drug candidate is identified with one of these issues (except the commercial limitations), normally, a new round of structureactivity or structure-property relationship (SAR/SPR) studies is carried out to generate a new chemical entity with improved profiles, and in most cases, such a process is time and labor-intensive. Alternatively, prodrug strategy can be leveraged to efficiently address associated drug developability issues without making enormous derivatives. Prodrug strategy has been demonstrated to be very successful and fruitful in drug development, with around 20% of approved drugs from 2008 through 2020 being clarified as prodrugs [4]. In recent years, prodrug strategy has also been leveraged to address the delivery issues associated with gasotransmitters, including NO, H2S, CO as well as SO2 [5-8]. In this thematic issue, six excellent reviews were included, focusing on varied prodrug strategies in addressing different drug developability issues associated with anticancer drugs, central nervous system (CNS) drugs, and gasotransmitters....

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Mahapatra, Dheeren Ku, et Lakshi Prosad Roy. « Empirical model for SAR ground clutter data ». IET Signal Processing 11, n^o 7 (septembre 2017) : 805–13. http://dx.doi.org/10.1049/iet-spr.2016.0351.

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Djurović, I., T. Thayaparan et Lj Stanković. « SAR imaging of moving targets using polynomial Fourier transform ». IET Signal Processing 2, n^o 3 (2008) : 237. http://dx.doi.org/10.1049/iet-spr:20070114.

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Djurović, I., C. Ioana, T. Thayaparan, L. Stanković, P. Wang, V. Popović et M. Simeunović. « Cubic-phase function evaluation for multicomponent signals with application to SAR imaging ». IET Signal Processing 4, n^o 4 (2010) : 371. http://dx.doi.org/10.1049/iet-spr.2009.0065.

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Wang, Yu, Yunhe Cao, Zhigang Peng et Hongtao Su. « Clutter suppression and GMTI for hypersonic vehicle borne SAR system with MIMO antenna ». IET Signal Processing 11, n^o 8 (octobre 2017) : 909–15. http://dx.doi.org/10.1049/iet-spr.2017.0193.

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Wang, Zelong, et Jubo Zhu. « Local low‐rank approach for parameter extraction of ocean internal wave from SAR image ». IET Signal Processing 13, n^o 1 (février 2019) : 1–6. http://dx.doi.org/10.1049/iet-spr.2018.5114.

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Kumar, Gaurav, Girendra Kumar Gautam, Ravi Kumar et Piyush Kumar Singhal. « A Review on Novel Omicron Virus ». Science Progress and Research 2, n^o 2 (11 avril 2022) : 580–82. http://dx.doi.org/10.52152/spr/2022.173.

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WHO in a recent study found a Nobel form of coronavirus in November. The variant name is given SAR- COV omicron (B.1.1.529). It is a higher number of mutation 26-32 spike. The first case of omicron was found in South Africa on November 9th. There is no further treatment that are available to cure omicron in recent time according to WHO and south African. South Africa has a higher number of patients in the globe and in the last few days, it spread all over the worldwide. It is significant that the previous vaccine is less effective against the Omicron variant but it protects the patient somewhere in hospitalization and death and is helpful in speed recovery. A few doctors say primary precautions should be taken like wearing mask, wearing PPE kit and using hand sanitiser etc in recent time number of vaccines available in the market but there is no sign it will cure completely but some level of effectiveness against the virus.

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Thayaparan, T., Lj Stankovic, C. Wernik et M. Dakovic. « Real-time motion compensation, image formation and image enhancement of moving targets in ISAR and SAR using S-method-based approach ». IET Signal Processing 2, n^o 3 (2008) : 247. http://dx.doi.org/10.1049/iet-spr:20070093.

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Horwitz, Matthew Allan. « Discovery Process Chemistry : An Innovation Hub at the Interface of Academia, the Pharmaceutical Industry, and Contract Research Organizations ». Synthesis, 5 août 2024. http://dx.doi.org/10.1055/a-2380-6425.

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Discovery Process Chemistry (DPC) is an emerging intersectoral space that is characterized by the development of new chemical reactions or syntheses which enable the efficient elucidation of structure-activity relationships (SARs) and structure-property relationships (SPRs), as well as a rapid transition to process development. Drug discovery and development are accelerated by such efforts and this has led chemists in academia and industry alike to place an increasing importance on these aims. In this Short Review, we explore recent advances in DPC and the impact that it can have on SAR/SPR interrogation and downstream drug development efforts.

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Lee, Hyun, Susan Boyle-Vavra, Jinhong Ren, Jamie A. Jarusiewicz, Lalit Kumar Sharma, Daniel T. Hoagland, Shaohui Yin et al. « Identification of Small Molecules Exhibiting Oxacillin Synergy through a Novel Assay for Inhibition of vraTSR Expression in Methicillin-Resistant Staphylococcus aureus ». Antimicrobial Agents and Chemotherapy 63, n^o 9 (17 juin 2019). http://dx.doi.org/10.1128/aac.02593-18.

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ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains that are resistant to all forms of penicillin have become an increasingly common and urgent problem threatening human health. They are responsible for a wide variety of infectious diseases ranging from minor skin abscesses to life-threatening severe infections. The vra operon that is conserved among S. aureus strains encodes a three-component signal transduction system (vraTSR) that is responsible for sensing and responding to cell wall stress. We developed a novel and multifaceted assay to identify compounds that potentiate the activity of oxacillin, essentially restoring efficacy of oxacillin against MRSA, and performed high-throughput screening (HTS) to identify oxacillin potentiators. HTS of 13,840 small-molecule compounds from an antimicrobial-focused Life Chemicals library, using the MRSA cell-based assay, identified three different inhibitor scaffolds. Checkerboard assays for synergy with oxacillin, reverse transcriptase PCR (RT-PCR) assays against vraR expression, and direct confirmation of interaction with VraS by surface plasmon resonance (SPR) further verified them to be viable hit compounds. A subsequent structure-activity relationship (SAR) study of the best scaffold with diverse analogs was utilized to improve potency and provides a strong foundation for further development.

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