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Parnham M.J.,Fraunhofer Institute for Molecular Biology and Applied Ecology | Sies H.,Heinrich Heine University Düsseldorf
Biochemical Pharmacology | Year: 2013

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one; PZ-51, DR-3305), is an organoselenium compound with glutathione peroxidase (GPx)-like, thiol-dependent, hydroperoxide reducing activity. As an enzyme mimic for activity of the selenoenzyme GPx, this compound has proved to be highly useful in research on mechanisms in redox biology. Furthermore, the reactivity of ebselen with protein thiols has helped to identify novel, selective targets for inhibitory actions on several enzymes of importance in pharmacology and toxicology. Importantly, the selenium in ebselen is not released and thus is not bioavailable, ebselen metabolites being excreted in bile and urine. As a consequence, initial concerns about selenium toxicity, fortunately, were unfounded. Potential applications in medical settings have been explored, notably in brain ischemia and stroke. More recently, there has been a surge in interest as new medical applications have been taken into consideration. The first publication on the biochemical effects of ebselen appeared 30 years ago (Müller et al. [4]), which prompted the authors to retrace the early development from their perspective. It is a fascinating example of fruitful interaction between research-oriented industry and academia. © ]2013 Elsevier Inc. All rights reserved.


Stoger E.,University of Natural Resources and Life Sciences, Vienna | Fischer R.,Fraunhofer Institute for Molecular Biology and Applied Ecology | Moloney M.,Rothamsted Research | Ma J.K.C.,St George's, University of London
Annual Review of Plant Biology | Year: 2014

Plant molecular pharming has emerged as a niche technology for the manufacture of pharmaceutical products indicated for chronic and ectious diseases, particularly for products that do not fit into the current industry-favored model of fermenter-based production campaigns. In this review, we explore the areas where molecular pharming can make the greatest impact, including the production of pharmaceuticals that have novel glycan structures or that cannot be produced efficiently in microbes or mammalian cells because they are insoluble or toxic. We also explore the market dynamics that encourage the use of molecular pharming, particularly for pharmaceuticals that are required in small amounts (such as personalized medicines) or large amounts (on a multi-ton scale, such as blood products and microbicides) and those that are needed in response to emergency situations (pandemics and bioterrorism). The impact of molecular pharming will increase as the platforms become standardized and optimized through adoption of good manufacturing practice (GMP) standards for clinical development, offering a new opportunity to produce inexpensive medicines in regional markets that are typically excluded under current business models. Copyright © 2014 by Annual Reviews.


Gul S.,Fraunhofer Institute for Molecular Biology and Applied Ecology | Hadian K.,Helmholtz Center Munich
Expert Opinion on Drug Discovery | Year: 2014

Introduction: Historically, small-molecule drug discovery projects have largely focused on the G-protein-coupled receptor, ion-channel and enzyme target classes. More recently, there have been successes demonstrating that protein-protein interactions (PPIs) can be targeted by small-molecules and that this strategy has the potential to provide appropriate specificity and selectivity. However, a disadvantage is that compounds that modulate PPIs are often associated with relatively weak affinities as the targeted interaction surfaces are often relatively large. Moreover, from a small-molecule screening perspective, a large proportion of the initial screening Hits are often false positives and these need to be identified and excluded in order to focus on genuine modulators of the PPI being investigated. Areas covered: The authors review previous efforts on PPI modulator drug discovery. Furthermore, they review assays that can be employed in small-molecule screening and/or Hit validation. The PPI assays are categorized as: i) low-throughput target-based biochemical assays, which are primarily employed for Hit validation at the post-screening stage; ii) high-throughput target-based biochemical assays that are suitable for screening campaigns; and iii) cell-based assays, which are suitable for high-throughput screening campaigns and/or Hit validation. Expert opinion: Modulating the interaction of PPIs offers the potential to develop novel drugs to treat a wide range of diseases. New assay technologies are continually being developed and it is anticipated that these will be able to be directly used for small-molecule screening campaigns in the future. © 2014 Informa UK, Ltd.


Buyel J.F.,RWTH Aachen | Buyel J.F.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Current Pharmaceutical Biotechnology | Year: 2015

Protein-based biopharmaceuticals are often produced in mammalian cell cultures, which are more expensive than microbial systems but capable of authentic post-translational modifications. The costs are lower if plants are used as an alternative platform to produce complex proteins such as monoclonal antibodies, vaccines and enzymes. This review highlights recent advances that have been achieved in plant-based biopharmaceutical production platforms in terms of expression strategies, product yields and process development. The first generation of plant-derived pharmaceuticals now entering the market is also discussed. Finally, the review considers the downstream processing of plant-derived pharmaceuticals which can account for up to 80% of the production costs. In this context, recent improvements in clarification and integrated process methods will have a strong impact on the economic feasibility of production, especially if supported by and combined with process analytical technology as part of the quality-by-design initiative. © 2015 Bentham Science Publishers.


Wacker M.G.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Journal of Pharmaceutical Sciences | Year: 2014

Nanomaterials have become part of formulation development in the pharmaceutical industry and offer exciting opportunities in the area of targeted drug delivery. But they may also exert unexpected toxicities and potentially pose a threat to human health and the environment. Since the Scientific Committee on Emerging and Newly Identified Health Risks recommended a definition of "nanomaterials" for implementation into the existing and upcoming regulatory framework in the European Union, a discussion about safety requirements of new nanoscale products has emerged. At the same time, the Food and Drug Administration of the United States still observes recent developments in this area. Although the impact on the pharmaceutical product chain is still uncertain, guidelines on risk assessment in food products and cosmetics are available and offer a preview of future developments in the regimens of pharmaceuticals. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.


Bortesi L.,RWTH Aachen | Fischer R.,RWTH Aachen | Fischer R.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Biotechnology Advances | Year: 2015

Targeted genome editing using artificial nucleases has the potential to accelerate basic research as well as plant breeding by providing the means to modify genomes rapidly in a precise and predictable manner. Here we describe the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system, a recently developed tool for the introduction of site-specific double-stranded DNA breaks. We highlight the strengths and weaknesses of this technology compared with two well-established genome editing platforms: zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). We summarize recent results obtained in plants using CRISPR/Cas9 technology, discuss possible applications in plant breeding and consider potential future developments. © 2015.


De Bruin N.M.W.J.,Fraunhofer Institute for Molecular Biology and Applied Ecology | Kruse C.G.,University of Amsterdam
Current Pharmaceutical Design | Year: 2015

5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5- HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyntyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer’s disease. © 2015, Bentham Science Publishers.


Jekat S.B.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Plant signaling & behavior | Year: 2012

Angiosperms transport their photoassimilates through sieve tubes, which comprise longitudinally-connected sieve elements. In dicots and also some monocots, the sieve elements contain parietal structural proteins known as phloem proteins or P-proteins. Following injury, P proteins disperse and accumulate as viscous plugs at the sieve plates to prevent the loss of valuable transport sugars. Tobacco (Nicotiana tabacum) P-proteins are multimeric complexes comprising subunits encoded by members of the SEO (sieve element occlusion) gene family. The existence of multiple subunits suggests that P-protein assembly involves interactions between SEO proteins, but this process is largely uncharacterized and it is unclear whether the different subunits perform unique roles or are redundant. We therefore extended our analysis of the tobacco P-proteins NtSEO1 and NtSEO2 to investigate potential interactions between them, and found that both proteins can form homomeric and heteromeric complexes in planta.


Fischer R.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Advances in biochemical engineering/biotechnology | Year: 2013

Bioethanol is currently produced by the fermentation of sugary and starchy crops, but waste plant biomass is a more abundant source because sugars can be derived directly from cellulose. One of the limiting steps in the biomass-to-ethanol process is the degradation of cellulose to fermentable sugars (saccharification). This currently relies on the use of bacterial and/or fungal cellulases, which tend to have low activity under biorefinery conditions and are easily inhibited. Some insect species feed on plant biomass and can efficiently degrade cellulose to produce glucose as an energy source. Although insects were initially thought to require symbiotic relationships with bacteria and fungi to break down cellulose, several species in the orders Dictyoptera, Orthoptera, and Coleoptera have now been shown to produce their own cellulases in the midgut or salivary glands, and putative cellulase genes have been identified in other orders. Insect cellulases often work in concert with cellulases provided by symbiotic microbiota in the gut to achieve efficient cellulolysis. We discuss the current status of insect cellulases and potential strategies that could be used to find novel enzymes and improve their efficiency.


Patent
Malaysian Palm Oil Board and Fraunhofer Institute for Molecular Biology and Applied Ecology | Date: 2013-08-07

The present disclosure relates to a protocol for the regeneration of Elaeis plants from protoplasts and to the genetic manipulation of the protoplasts to introduce or facilitate expression of desired properties and beneficial traits in Elaeis plants.

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