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Drug Discovery Today

Bapi Gorain, Muktika Tekade, Prashant Kesharwani, Arun K Iyer, Kiran Kalia, Rakesh Kumar Tekade
To avoid tissue rejection during organ transplantation, research has focused on the use of tissue engineering to regenerate required tissues or organs for patients. The biomedical applications of hyperbranched, multivalent, structurally uniform, biocompatible dendrimers in tissue engineering include the mimicking of natural extracellular matrices (ECMs) in the 3D microenvironment. Dendrimers are unimolecular architects that can incorporate a variety of biological and/or chemical substances in a 3D architecture to actively support the scaffold microenvironment during cell growth...
February 17, 2017: Drug Discovery Today
Natalia G Bednarska, Brendan W Wren, Sam J Willcocks
Glycosylation is one of the most prevalent post-translational modifications of a protein, with a defining impact on its structure and function. Many of the proteins involved in the innate or adaptive immune response, including cytokines, chemokines, and antimicrobial peptides (AMPs), are glycosylated, contributing to their myriad activities. The current availability of synthetic coupling and glycoengineering technology makes it possible to customise the most beneficial glycan modifications for improved AMP stability, microbicidal potency, pathogen specificity, tissue or cell targeting, and immunomodulation...
February 14, 2017: Drug Discovery Today
Umberto M Musazzi, Valentina Marini, Antonella Casiraghi, Paola Minghetti
The growing application of nanomaterials in healthcare products (i.e., cosmetics, medical devices, and medicinal products) has encouraged the upgrade of the regulatory framework within the European Community (EC) to better control their use and manage the risk of negative effects on human health and environment. Unfortunately, despite the efforts of European Authorities, the current legislation is still stratified and several criticisms remain because of the lack of well-established scientific knowledge on nanomaterials...
February 9, 2017: Drug Discovery Today
Siem van der Laan, Nicolas Salvetat, Dinah Weissmann, Franck Molina
Unanticipated adverse drug reactions (ADRs) on the central nervous system are a major cause of clinical attrition and market withdrawal. Current practices for their prospective assessment still lean on extensive analysis of rodent behaviour despite their highly controversial predictive value. Human-derived in vitro models that objectively quantify mechanism-related biomarkers can greatly contribute to better ADR prediction at early developmental stages. Adenosine-to-inosine RNA editing constitutes a physiological cellular process that translates environmental cues by regulating protein function at the synaptic level in health and disease...
February 7, 2017: Drug Discovery Today
Elena Molokanova, Mark Mercola, Alex Savchenko
The current mandate for the drug discovery industry is to develop more efficient drugs faster while reducing the costs associated with their development. Incorporation of cell stimulation technologies during screening assays is expected to revolutionize the discovery of novel drugs as well as safety pharmacology. In this review, we highlight 'classical' and emerging cell stimulation technologies that provide the ability to evaluate the effects of drug candidates on cells in different functional states to assess clinically relevant phenotypes...
February 4, 2017: Drug Discovery Today
Bertil Schmidt, Andreas Hildebrandt
The progress of next-generation sequencing has a major impact on medical and genomic research. This high-throughput technology can now produce billions of short DNA or RNA fragments in excess of a few terabytes of data in a single run. This leads to massive datasets used by a wide range of applications including personalized cancer treatment and precision medicine. In addition to the hugely increased throughput, the cost of using high-throughput technologies has been dramatically decreasing. A low sequencing cost of around US$1000 per genome has now rendered large population-scale projects feasible...
February 2, 2017: Drug Discovery Today
Xuan Chi, Philip Gatti, Thomas Papoian
Oligonucleotide-based therapy is an active area of drug development designed to treat a variety of gene-specific diseases. Two of the more promising platforms are the antisense oligonucleotides (ASOs) and short interfering RNAs (siRNAs), both of which are often directed against similar targets. In light of recent reports on clinical trials of severe thrombocytopenia with two different ASO drugs and increased peripheral neuropathy with an siRNA drug, we compared and contrasted the specific safety characteristics of these two classes of oligonucleotide therapeutic...
January 31, 2017: Drug Discovery Today
Stella Totti, Spyros I Vernardis, Lisiane Meira, Pedro A Pérez-Mancera, Eithne Costello, William Greenhalf, Daniel Palmer, John Neoptolemos, Athanasios Mantalaris, Eirini G Velliou
Pancreatic cancer is one of the most aggressive and lethal human malignancies. Drug therapies and radiotherapy are used for treatment as adjuvants to surgery, but outcomes remain disappointing. Advances in tissue engineering suggest that 3D cultures can reflect the in vivo tumor microenvironment and can guarantee a physiological distribution of oxygen, nutrients, and drugs, making them promising low-cost tools for therapy development. Here, we review crucial structural and environmental elements that should be considered for an accurate design of an ex vivo platform for studies of pancreatic cancer...
January 30, 2017: Drug Discovery Today
Joana Costa-Gouveia, José A Aínsa, Priscille Brodin, Ainhoa Lucía
Therapeutic approaches using nanoparticles are being successfully used in foods and in several fields of medicine, including infectious diseases. Regarding tuberculosis (TB) treatment, nanoparticles can be a useful strategy for two distinct applications: (i) for their intrinsic antimycobacterial activity; (ii) as vehicles for known antitubercular drugs to allow reduction of dose- and drug-associated side-effects and administration via user-friendly administration routes such as pulmonary or oral ones. Promising results were obtained in vitro and in animal Mycobacterium tuberculosis models and need now to be translated into clinical drug candidates...
January 27, 2017: Drug Discovery Today
Glenn P Carroll, Sanjay Srivastava, Adam S Volini, Marta M Piñeiro-Núñez, Tatiana Vetman
Today, most pharmaceutical companies complement their traditional R&D models with some variation on the Open Innovation (OI) approach in an effort to better access global scientific talent, ideas and hypotheses. Traditional performance indicators that measure economic returns from R&D through commercialization are often not applicable to the practical assessment of these OI approaches, particularly within the context of early drug discovery. This leaves OI programs focused on early R&D without a standard assessment framework from which to evaluate overall performance...
January 27, 2017: Drug Discovery Today
Alessandro Dalpiaz, Barbara Pavan, Valeria Ferretti
Poorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability...
January 24, 2017: Drug Discovery Today
Pierre-André Billat, Emilie Roger, Sébastien Faure, Frédéric Lagarce
The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models)...
January 20, 2017: Drug Discovery Today
Joan Mayol-Llinàs, Adam Nelson, William Farnaby, Andrew Ayscough
There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood-brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs...
January 20, 2017: Drug Discovery Today
Abel Soto-Gamez, Marco Demaria
Organismal aging is a multifactorial process characterized by the onset of degenerative conditions and cancer. One of the key drivers of aging is cellular senescence, a state of irreversible growth arrest induced by many pro-tumorigenic stresses. Senescent cells accumulate late in life and at sites of age-related pathologies, where they contribute to disease onset and progression through complex cell and non-cell autonomous effects. Here, we summarize the mechanisms by which cellular senescence can promote aging, and we offer an extensive description of current potential pharmacological interventions for senescent cells, highlighting limitations and suggesting alternatives...
January 19, 2017: Drug Discovery Today
Amir Abbas Momtazi, Maciej Banach, Matteo Pirro, Evan A Stein, Amirhossein Sahebkar
Diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as effective low-density lipoprotein cholesterol-lowering compounds. Although the results of available epidemiological, preclinical, and clinical studies suggest a positive association of plasma PCSK9 levels with glycemic parameters and risk of type 2 DM (T2DM), genetic findings have shown contradictory results. Overall, the impact of PCSK9 inhibitors on glycemic control parameters in patients with DM remains unclear...
January 19, 2017: Drug Discovery Today
Alessandro Giuliani
There is a neat distinction between general purpose statistical techniques and quantitative models developed for specific problems. Principal Component Analysis (PCA) blurs this distinction: while being a general purpose statistical technique, it implies a peculiar style of reasoning. PCA is a 'hypothesis generating' tool creating a statistical mechanics frame for biological systems modeling without the need for strong a priori theoretical assumptions. This makes PCA of utmost importance for approaching drug discovery by a systemic perspective overcoming too narrow reductionist approaches...
January 19, 2017: Drug Discovery Today
Liliana Rodrigues, Tanya Parish, Meenakshi Balganesh, José A Ainsa
In mycobacteria, it was assumed that efflux pumps only had a marginal role in drug resistance. In recent years, owing to the need to find novel drugs against multidrug-resistant tuberculosis, it has become clear that efflux should not be ignored. Although efflux inhibitors have been very useful for characterizing in vitro the properties of efflux pumps, their usefulness in vivo is limited because of their toxicity. Alternatively, programs aimed at discovering novel drugs for treating tuberculosis should implement strategies to characterize efflux liability of candidate drugs...
January 13, 2017: Drug Discovery Today
David J Ponting, Ernest Murray, Anthony Long
How confident can we be in the assignment of metabolite structures? Are the analytical techniques used sufficient to support hypotheses about what is being formed? In this Feature, we discuss the results of an extensive survey into the analytical techniques used, and their value in the characterisation of metabolites. The survey covers the structures of over 16000 metabolites formed from 1732 query compounds, covering over 35 years of the literature and a variety of journals. The value of different characterisation techniques is considered, alongside or in the absence of synthetic standards...
January 11, 2017: Drug Discovery Today
Yi Lu, Jianping Qi, Xiaochun Dong, Weili Zhao, Wei Wu
There has been significant research interest in, and development of, nanocrystals in recent years for the delivery of poorly water-soluble drugs via various routes. However, there is a common misinterpretation of nanocrystallization as an approach to modulate, and more specifically to enhance, the dissolution of drug crystals. Nevertheless, it is possible for nanocrystals to interact with biological tissues because nanocrystals can survive for a longer duration in vivo compared with solution counterparts. Therefore, understanding the in vivo fate of nanocrystals and determining its contribution to efficacy is of tremendous significance for optimizing the performance of nanocrystals...
January 11, 2017: Drug Discovery Today
Pierre-Louis Destruel, Ni Zeng, Marc Maury, Nathalie Mignet, Vincent Boudy
In situ gelling delivery systems for the ocular administration of drugs has been a major focus of research over the past two decades, improving the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration. This drug delivery strategy results in high ocular bioavailability by avoiding rapid precorneal clearance resulting from nasolacrimal drainage and eye blinking. However, the development of such unconventional forms requires many parameters to be mastered, such as gelation time, viscoelastic behavior, mucoadhesion, and sustained release...
December 23, 2016: Drug Discovery Today
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