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Drug Discovery Today. Technologies

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https://www.readbyqxmd.com/read/30205881/the-multiplexed-crispr-targeting-platforms
#1
REVIEW
Jian Cao, Qian Xiao, Qin Yan
The discovery and engineering of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in the past several years have revolutionized biomedical research. The CRISPR technology showed great potential to advance detection, prevention, and treatment of human diseases in the near future. Compared to previous developed genome editing approaches, such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), the CRISPR-based systems have numerous advantages. One example is that the CRISPR systems can be easily adopted to efficiently target multiple genes simultaneously...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205880/crispr-cas9-disease-models-in-zebrafish-and-xenopus-the-genetic-renaissance-of-fish-and-frogs
#2
REVIEW
Thomas Naert, Kris Vleminckx
The speed by which clinical genomics is currently identifying novel potentially pathogenic variants is outperforming the speed by which these can be functionally (genotype-phenotype) annotated in animal disease models. However, over the past few years the emergence of CRISPR/Cas9 as a straight-forward genome editing technology has revolutionized disease modeling in vertebrate non-mammalian model organisms such as zebrafish, medaka and Xenopus. It is now finally possible, by CRISPR/Cas9, to rapidly establish clinically relevant disease models in these organisms...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205879/crispr-cas9-genome-engineering-in-hematopoietic-cells
#3
REVIEW
Duran Sürün, Harald von Melchner, Frank Schnütgen
The development of genome editing tools capable of modifying specific genomic sequences with unprecedented accuracy has opened up a wide range of new possibilities in targeted gene manipulation. In particular, the CRISPR/Cas9 system, a repurposed prokaryotic adaptive immune system, has been widely adopted because of its unmatched simplicity and flexibility. In this review we discuss achievements and current limitations of CRISPR/Cas9 genome editing in hematopoietic cells with special emphasis on its potential use in ex vivo gene therapy of monogenic blood disorders, HIV and cancer...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205878/developing-precision-medicine-using-scarless-genome-editing-of-human-pluripotent-stem-cells
#4
REVIEW
Benjamin Steyer, Evan Cory, Krishanu Saha
Many avenues exist for human pluripotent stem cells (hPSCs) to impact medical care, but they may have their greatest impact on the development of precision medicine. Recent advances in genome editing and stem cell technology have enabled construction of clinically-relevant, genotype-specific "disease-in-a-dish" models. In this review, we outline the use of genome-edited hPSCs in precision disease modeling and drug screening as well as describe methodological advances in scarless genome editing. Scarless genome-editing approaches are attractive for genotype-specific disease modeling as only the intended DNA base-pair edits are incorporated without additional genomic modification...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205877/crispr-cas9-genome-surgery-for-retinal-diseases
#5
REVIEW
Christine L Xu, Karen Sophia Park, Stephen H Tsang
Retinal diseases that impair vision can impose heavy physical and emotional burdens on patients' lives. Currently, clustered regularly interspaced short palindromic repeats (CRISPR) is a prevalent gene-editing tool that can be harnessed to generate disease model organisms for specific retinal diseases, which are useful for elucidating pathophysiology and revealing important links between genetic mutations and phenotypic defects. These retinal disease models are fundamental for testing various therapies and are indispensible for potential future clinical trials...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205876/crispr-cas9-mediated-genome-editing-in-human-stem-cell-derived-cardiomyocytes-applications-for-cardiovascular-disease-modelling-and-cardiotoxicity-screening
#6
REVIEW
Effimia Christidi, Haojun Margaret Huang, Liam R Brunham
Cardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug-induced cardiotoxicity. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) have provided a major advance to our ability to study these conditions. Combined with efficient genome editing technologies, such as CRISPR/Cas9, we now have the ability to study with greater resolution the genetic causes and underlying mechanisms of inherited and drug-induced cardiotoxicity, and to investigate new treatments...
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30205875/crispr-cas9-homologous-recombination-hr
#7
EDITORIAL
Milena Bellin
No abstract text is available yet for this article.
August 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103868/modifying-the-physicochemical-properties-of-nsaids-for-nasal-and-pulmonary-administration
#8
REVIEW
P Szabó-Révész
This review focuses on nasal and pulmonary delivery of NSAIDs (non-steroidal anti-inflammatory drugs) for fast-onset analgesia, for the potential prevention of Alzheimer's disease (AD), as well as for an add-on treatment in cystic fibrosis (CF) and non-small cell lung cancer (NSCLC). I discuss how the physicochemical properties of NSAIDs can be modified with respect to the biological characteristics of the target site. Innovative technology and/or dosage forms can promote an effective therapy.
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103867/physico-chemical-characterization-of-self-emulsifying-drug-delivery-systems
#9
REVIEW
Zoltán Ujhelyi, Miklós Vecsernyés, Pálma Fehér, Dóra Kósa, Petra Arany, Dániel Nemes, Dávid Sinka, Gábor Vasvári, Ferenc Fenyvesi, Judit Váradi, Ildikó Bácskay
Self-emulsifying drug delivery systems (SEDDS) are regarded as a potential implement for oral delivery of water insoluble APIs to overcome their poor and irregular bioavailability. The correlation between the physicochemical parameters and the behavior of self-emulsifying drug delivery systems was established. The objective of this study was to summarize these physicochemical factors characterized SEDDS. Determination of self-emulsification process and ternary phase diagram are the basis of preparations. The position of APIs in SEDDS inclusion can be determined by dye solubilisation test...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103866/matrix-systems-for-oral-drug-delivery-formulations-and-drug-release
#10
REVIEW
Gábor Vasvári, József Kalmár, Péter Veres, Miklós Vecsernyés, Ildikó Bácskay, Pálma Fehér, Zoltán Ujhelyi, Ádám Haimhoffer, Ágnes Rusznyák, Ferenc Fenyvesi, Judit Váradi
In this current article matrix formulations for oral drug delivery are reviewed. Conventional dosage forms and novel applications such as 3D printed matrices and aerogel matrices are discussed. Beside characterization, excipients and matrix forming agents are also enlisted and classified. The incorporated drug could exist in crystalline or in amorphous forms, which makes drug dissolution easily tunable. Main drug release mechanisms are detailed and reviewed to support rational design in pharmaceutical technology and manufacturing considering the fact that R&D members of the industry are forced to obtain knowledge about excipients and methods pros and cons...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103865/log-p-as-a-tool-in-intramolecular-hydrogen-bond-considerations
#11
REVIEW
Giulia Caron, Maura Vallaro, Giuseppe Ermondi
Intramolecular hydrogen bonding (IMHB) considerations are gaining relevance in drug discovery and a molecular descriptor which can predict very early the capacity of a compound to form IMHB is needed to speed up the optimization process of drug candidates. Although log Poct is largely used for optimization purposes, in this paper we firstly use the Block Relevance (BR) analysis to theoretically show how log Poct is not a convenient choice to assess IMHB properties of candidates. Then we discuss the limits of log Poct and introduce Δlog Poct-tol , i...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103864/experimental-and-pk-a-prediction-aspects-of-tautomerism-of-drug-like-molecules
#12
REVIEW
Yvonne Connolly Martin
Molecules that can tautomerize are a challenge to scientists because one must consider the possible tautomers in most tasks involving chemical structures: for example, searching databases, interpreting experimental property measurements, calculating properties, virtual screening, and analyzing structure-bioactivity relationships. The challenge in interpreting property measurements such as pKa values feeds into the general lack of extensive information not only of the relative tautomer stability in water but also the properties of the individual tautomers...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103863/automated-techniques-in-pk-a-determination-low-medium-and-high-throughput-screening-methods
#13
REVIEW
Christophe Dardonville
Drug discovery programs that generate hundreds of new molecular entities need efficient methodologies for physicochemical profiling. Several high-throughput methods for pKa screening have been developed in the last 15 years to determine this key physicochemical parameter. Separation techniques such as HPLC-MS or capillary electrophoresis are particularly well-suited due to their high throughput and capacity to deal with impure or complex samples. In addition, potentiometric and (mostly) UV-metric-based methods (plate-based and automated systems), find their place as very precise methodologies for pKa determination despite of somewhat lower throughput...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103862/the-influence-and-manipulation-of-acid-base-properties-in-drug-discovery
#14
REVIEW
David T Manallack, Elizabeth Yuriev, David K Chalmers
There is a growing awareness of the importance of acid/base properties in medicinal chemistry research. In many drug classes, ionisable groups are present that make critical interactions with the receptor and are essential for potency. Yet the presence of these groups may cause problems with oral bioavailability, pharmacokinetics, or toxicity. Manipulating pKa values during drug development or applying pro-drug techniques are strategies that can overcome potential deficits in a variety of these areas. Knowledge of drug ionisation states coupled with a consideration of pH-specific cellular environments can be used advantageously to target chemoresistance...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103861/brief-overview-of-solubility-methods-recent-trends-in-equilibrium-solubility-measurement-and-predictive-models
#15
REVIEW
Árpád Könczöl, Gergő Dargó
Solubility is a crucial physicochemical parameter affecting the whole process of drug discovery and development. Thus, understanding of the methods and concepts to measure and predict this propensity are of utmost importance for the pharmaceutical scientist. Despite their inherent limitations, kinetic solubility screening methods became routine assays by mimicking bioassay conditions and guiding the lead optimization process. In contrast, thermodynamic solubility methods show a clear evolution: miniaturized high throughput assays coupled to analytical techniques such as solid-state characterization, ultra performance liquid chromatography, or polychromatic turbidimetry, have been developed, thereby enabling a more complex physicochemical profiling at the early discovery stage...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103860/different-types-applications-and-limits-of-enabling-excipients-of-pharmaceutical-dosage-forms
#16
REVIEW
Barnabás Palcsó, Romána Zelkó
Along with the development of novel drug delivery systems the material science is also advancing. Conventional and novel synthetic or natural excipients provide opportunities to design dosage forms of the required features including their bioavailability. Emerging trends in the design and development of drug products indicate an increasing need for the functionality-related characterization of excipients. The purpose of this review is to provide an overview of different types of excipients in relation to their application possibilities in various dosage forms with special focus on the enabling excipients...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103859/automated-assays-for-thermodynamic-equilibrium-solubility-determination
#17
REVIEW
Tomás Sou, Christel A S Bergström
Solubility is a crucial physicochemical property for drug candidates and is important in both drug discovery and development. Poor solubility is detrimental to absorption after oral administration and can mask compound activity in bioassays in various ways. Hence, solubility liabilities should ideally be identified as early as possible in the drug development process. With the increasing number of compounds as potential drug candidates, automated thermodynamic solubility assays for high throughput screening enabling rapid evaluation of a large number of compounds are becoming increasingly important...
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/30103858/physicochemical-characterisation-in-drug-discovery
#18
EDITORIAL
György T Balogh
No abstract text is available yet for this article.
July 2018: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249241/constrained-cell-penetrating-peptides
#19
REVIEW
S A Bode, D W P M Löwik
In this review we provide an overview of recent developments in the field of cell penetrating peptides (CPPs) on research that aims to achieve better control over their transduction properties - one of the big challenges - by means of restraining them. Three different constraining strategies are presented: triggerable activation, backbone rigidification and macrocyclization. Each of these methods have their opportunities in gaining control over CPP activity and selectivity.
December 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29249240/recent-advances-in-the-synthesis-of-cyclic-pseudopeptides
#20
REVIEW
Serge Zaretsky, Andrei K Yudin
Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non-peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry...
December 2017: Drug Discovery Today. Technologies
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