Global challenges in stem cell research and the many roads ahead

The field of stem cell research has grown to include a vibrant international community of scientists and clinicians who come from both academia and industry and who strive to shed light on the biology of these remarkable cells and find applications in drug discovery, disease modeling, and regenerative medicine.     

Small molecule microarrays: recent advances and applications

Directed or exploratory drug development programs constantly seek robust screening platforms for the high fidelity identification and validation of potential targets. Small-molecule microarrays (SMMs) have risen to this call by elegantly forging the capability of combinatorial chemistry in producing myriad compounds with the powerful throughput afforded by microarrays. This synergism offers scientists a versatile tool for rapid compound analysis and discovery. Microarrays of small molecules have already been successfully applied in important areas ranging from protein profiling to the discovery of therapeutic leads. Recent interesting developments towards improved immobilization strategies and library creation methods, together with novel advances herein described, have set the stage for SMMs to take on wider and more routine applications in academia and industry. As a rapidly maturing technology, SMMs pave the way forward in high-throughput exploration, both in the identification of biologically significant natural and synthetic small molecules and in harnessing their vast potential towards medicinal and diagnostic applications.     

Realizing the promise of population biobanks: a new model for translation

The promise of science lies in expectations of its benefits to societies and is matched by expectations of the realisation of the significant public investment in that science. In this paper, we undertake a methodological analysis of the science of biobanking and a sociological analysis of translational research in relation to biobanking. Part of global and local endeavours to translate raw biomedical evidence into practice, biobanks aim to provide a platform for generating new scientific knowledge to inform development of new policies, systems and interventions to enhance the public’s health. Effectively translating scientific knowledge into routine practice, however, involves more than good science. Although biobanks undoubtedly provide a fundamental resource for both clinical and public health practice, their potentiating ontology—that their outputs are perpetually a promise of scientific knowledge generation—renders translation rather less straightforward than drug discovery and treatment implementation. Biobanking science, therefore, provides a perfect counterpoint against which to test the bounds of translational research. We argue that translational research is a contextual and cumulative process: one that is necessarily dynamic and interactive and involves multiple actors. We propose a new multidimensional model of translational research which enables us to imagine a new paradigm: one that takes us from bench to bedside to backyard and beyond, that is, attentive to the social and political context of translational science, and is cognisant of all the players in that process be they researchers, health professionals, policy makers, industry representatives, members of the public or research participants, amongst others.     

Bridging the Valley of Death of therapeutics for neurodegeneration

Neurodegenerative diseases are the sixth leading cause of death in the US. The market for disease-modifying drugs is enormous, but no drug exists. Academic scientists are increasingly pursuing the discovery and development of therapeutics. Their progress could potentially reduce the risk of failure sufficiently to warrant greater industry investment and movement of leads into clinical trials. Here we consider the many obstacles to the development of therapeutics for neurodegenerative disease within academia, with a special focus on organizational issues.     

Fragment-based approaches in drug discovery and chemical biology

Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, β-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.     

High-content screening in infectious diseases

The last decade has seen the development of automated microscopy and its adaptation for various areas of research, particularly infectious disease. Most of the high-content screening (HCS) platforms now integrate all of the following necessary steps: automated pipettes for assay miniaturization in 384-well plates, automated image acquisition and data storage and analysis. HCS was initially associated with RNA interference genetic screens for identifying host factors involved in host-pathogen interactions. More recently, both in academia and in industry, HCS has been adapted for drug discovery purposes. High-content analysis enables intracellular tracking of viral particles to profile the antiviral mechanisms of each compound. Adaptation to high-throughput screening in bacteriology and parasitology has already led to the discovery of new types of host-specific inhibitors that differ from those inhibitors that act directly on microbes.     

TRAIN: Training through Research Application Italian iNitiative

Training through Research Application Italian iNitiative (TRAIN) is a mobility program financed under the EU action called "Cofinancing of regional, national and international programs" (COFUND) of the European Commission Seventh Framework Program (FP7) - People, and has been designed to encourage the promotion and development of international programs of research through mobility at various stages of research careers. The aim of TRAIN is to improve translational skills in the field of cancer by promoting a three-year international mobility program assigning a total of 51 fellowships subdivided into incoming, outgoing and reintegration fellowships.?The TRAIN proposal has been submitted in February 2009 to the European Commission in reply to the 2008 FP7-PEOPLE-COFUND call and has been successfully evaluated. TRAIN is addressed to postdoctoral scientists or scientists who have at least four years' full-time equivalent research experience and who wish to improve their careers spending one year abroad. The mobility program is open also to non-Italian experienced scientists wishing to spend one year in an Italian research center or private company. Part of the scheme is targeted to experienced Italian scientists who have completed at least three years of research in a foreign country and are interested in returning to Italy.?TRAIN is part of an overall Italian strategy outlined by the International Program of the Italian Cancer Network "Alleanza Contro il Cancro" to promote Italian participation in the building of the European Area for translational cancer research and to enhance the interaction between academy and industry.     

Advances in and applications of proteasome inhibitors

With the recent US Food and Drug Administration approval of bortezomib (Velcade) for the treatment of relapsed multiple myeloma, the proteasome has emerged as a new therapeutic target with diverse pathology. Drug discovery programs in academia and the pharmaceutical industry have developed a range of low nanomolar synthetic and natural inhibitors of the 20S proteasome core particle that have entered human clinical trials as significant anti-cancer and anti-inflammatory leads. Moreover, proteasome inhibitors continue to serve as valuable research tools in cellular biology through the elucidation of important biological processes associated with the ubiquitin-proteasome pathway of protein degradation. This review will highlight recent advances in the development and application of proteasome inhibitors.     

Drug discovery in academia

Drug discovery and development is generally done in the commercial rather than the academic realm. Drug discovery involves target discovery and validation, lead identification by high-throughput screening, and lead optimization by medicinal chemistry. Follow-up preclinical evaluation includes analysis in animal models of compound efficacy and pharmacology (ADME: administration, distribution, metabolism, elimination) and studies of toxicology, specificity, and drug interactions. Notwithstanding the high-cost, labor-intensive, and non-hypothesis-driven aspects of drug discovery, the academic setting has a unique and expanding niche in this important area of investigation. For example, academic drug discovery can focus on targets of limited commercial value, such as third-world and rare diseases, and on the development of research reagents such as high-affinity inhibitors for pharmacological "gene knockout" in animal models ("chemical genetics"). This review describes the practical aspects of the preclinical drug discovery process for academic investigators. The discovery of small molecule inhibitors and activators of the cystic fibrosis transmembrane conductance regulator is presented as an example of an academic drug discovery program that has yielded new compounds for physiology research and clinical development. high-throughput screening; drug development; pharmacology; fluorescence; cystic fibrosis transmembrane conductance regulator     

Proteomic approaches for the global analysis of proteins

Improvements in technology that allow miniaturization and high-throughput analyses of thousand of genes and gene products have changed the focus and scope of research and development in both academia and industry. It is now possible to study entire proteomes with the goals of elucidating protein expression, subcellular localization, biochemical activities, and their regulation. Alterations in different cell types and conditions and in normal and disease states can be revealed. This wealth of information not only has facilitated our basic understanding of many biological processes but also has enormous potential for drug discovery and development.     

Drug discovery and development for neglected parasitic diseases

Diseases caused by tropical parasites affect hundreds of millions of people worldwide but have been largely neglected for drug development because they affect poor people in poor regions of the world. Most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. This review will summarize efforts to reinvigorate the drug development pipeline for these diseases, which is driven in large part by support from major philanthropies. The organisms responsible for these diseases have a fascinating biology, and many potential biochemical targets are now apparent. These neglected diseases present unique challenges to drug development that are being addressed by new consortia of scientists from academia and industry.     

Assuring the quality, safety, and efficacy of DNA vaccines

Scientists in academia whose research is aimed at the development of a novel vaccine or approach to vaccination may not always be fully aware of the regulatory process by which a candidate vaccine becomes a licensed product. It is useful for such scientists to be aware of these processes as the development of a novel vaccine could be problematic owing to the starting material often being developed in a research laboratory under ill-defined conditions. This paper examines the regulatory process with respect to the development of a DNA vaccine. DNA vaccines present unusual safety considerations that must be addressed during preclinical safety studies, including adverse immunopathology, genotoxicity through integration into a vaccinees chromosomes, and the potential for the formation of anti-DNA antibodies.     

药物临床前研究与转化医学——实验动物的应用与动物实验

本文讨论了药物临床前研究与实验动物和动物模型之间的关系,探讨了实验动物和动物模型在新药研发过程中实现转化研究的要求和条件.讨论了实验动物质量对新药研发的影响,分析了实验动物质量的影响因素;讨论了实验动物模型的主要类型和特点,分析了进行实验动物模型研究的要点和要求;分析了动物模型与新药研发过程中实现转化研究的条件,提出加强转化研究需要实验动物和动物模型研究的支撑.     

Drug discovery for malaria: a very challenging and timely endeavor

The prevalence of resistance to known antimalarial drugs has resulted in the expansion of antimalarial drug discovery efforts. Academic and nonprofit institutions are partnering with the pharmaceutical industry to develop new antimalarial drugs. Several new antimalarial agents are undergoing clinical trials, mainly those resurrected from previous antimalarial drug discovery programs. Novel antimalarials are being advanced through the drug development process, of course, with the anticipated high failure rate typical of drug discovery. Many of these are summarized in this review. Mechanisms for funding antimalarial drug discovery and genomic information to aid drug target selection have never been better. It remains to be seen whether ongoing efforts will be sufficient for reducing malaria burden in the developing world.     

How many animals are used for SARS‐CoV‐2 research?: An overview on animal experimentation in pre‐clinical and basic research

Non‐technical summaries of research projects allow tracking the numbers and purpose of animal experiments related to SARS‐CoV2 research so as to provide greater transparency on animal use. Subject Categories: Economics, Law & Politics, Pharmacology & Drug Discovery, Science Policy & Publishing

The COVID‐19 pandemic has accelerated biomedical research and drug development to an unprecedented pace. Governments worldwide released emergency funding for biomedical research that allowed scientists to focus on COVID‐19 and related drug and vaccine development. As a result, a flood of scientific articles on SARS‐CoV‐2 and COVID‐19 was published since early 2020. More importantly though, within less than 2 years, scientists in academia and industry developed vaccines against the virus from scratch: Several vaccines have now received regulatory approval and are being mass produced to immunize the human population worldwide.This colossal success of science rests in large part on the shoulders of animals that were used in basic and pre‐clinical research and regulatory testing. Notwithstanding, animal experimentation has remained a highly controversial and heated topic between advocates for research and animal rights activists. During the past decades, European policymakers responded to the debate by enacting stricter regulations, which inevitably has increased the bureaucratic hurdles for experimentation on animals. Scientists have for long spoken out against this additional burden, arguing that both basic and translational researches to improve human health crucially relies on animal experimentation—as the COVID‐19 pandemic aptly demonstrated (Genzel et al, 2020).     

Open Access Target Validation Is a More Efficient Way to Accelerate Drug Discovery

There is a scarcity of novel treatments to address many unmet medical needs. Industry and academia are finally coming to terms with the fact that the prevalent models and incentives for innovation in early stage drug discovery are failing to promote progress quickly enough. Here we will examine how an open model of precompetitive public–private research partnership is enabling efficient derisking and acceleration in the early stages of drug discovery, whilst also widening the range of communities participating in the process, such as patient and disease foundations.     

AutoClickChem: click chemistry in silico

Academic researchers and many in industry often lack the financial resources available to scientists working in "big pharma." High costs include those associated with high-throughput screening and chemical synthesis. In order to address these challenges, many researchers have in part turned to alternate methodologies. Virtual screening, for example, often substitutes for high-throughput screening, and click chemistry ensures that chemical synthesis is fast, cheap, and comparatively easy. Though both in silico screening and click chemistry seek to make drug discovery more feasible, it is not yet routine to couple these two methodologies. We here present a novel computer algorithm, called AutoClickChem, capable of performing many click-chemistry reactions in silico. AutoClickChem can be used to produce large combinatorial libraries of compound models for use in virtual screens. As the compounds of these libraries are constructed according to the reactions of click chemistry, they can be easily synthesized for subsequent testing in biochemical assays. Additionally, in silico modeling of click-chemistry products may prove useful in rational drug design and drug optimization. AutoClickChem is based on the pymolecule toolbox, a framework that may facilitate the development of future python-based programs that require the manipulation of molecular models. Both the pymolecule toolbox and AutoClickChem are released under the GNU General Public License version 3 and are available for download from http://autoclickchem.ucsd.edu.     

药物蛋白质组学与药物发现

21世纪,科学家面临着从基因组到蛋白质组的转变,蛋白质组学是基因组和药物发现的效率。药物蛋白质组学研究不仅有助于发现治疗的可能靶点,也将明显提高药物发现的效率。药物蛋白质组学的研究内容,在临床前包括发现新的治疗靶点和发现针对所有靶点的全部化合物,在临床研究方面应包括药物作用的特异蛋白作为诊断和治疗的标志,或以蛋白质谱的差异来分类者。本文主要综述了蛋白质组学在药物靶点的发现和确认,以有药物发现过程中最有关的技术物研究进展。