Biotech Crossroads: Singapore

Cover illustration: Singapore Biotech Crossroads, a BTJ special issue edited by Dr. Michael Entzeroth, Pharma Resources Asia Pte Ltd, Singapore. Highlights include articles about Singapore's biomedical sciences landscape, UK-Singapore relationships in life sciences, oncology and drug discovery, bioprocessing technology and much more. Image©Photodisc Inc.     

Novel Approaches to Drug Discovery in Signal Transduction

Cover illustration: This issue of BTJ contains three special articles featuring novel approaches to drug discovery in signal transduction. On the one hand side, there is a focus on cell-based assays for GPCRs – one of the main drug targets and technologies for label-free cell-based assays. On the other hand, it is shown how computational approaches are important to predict binding activity of chemical structures and thus support drug discovery. Image@Photodisc/Getty images.     

Drug discovery for parasitic diseases: powered by technology,enabled by pharmacology,informed by clinical science

While prevention is a bedrock of public health, innovative therapeutics are needed to complement the armamentarium of interventions required to achieve disease control and elimination targets for neglected diseases. Extraordinary advances in drug discovery technologies have occurred over the past decades, along with accumulation of scientific knowledge and experience in pharmacological and clinical sciences that are transforming many aspects of drug R&D across disciplines. We reflect on how these advances have propelled drug discovery for parasitic infections, focusing on malaria, kinetoplastid diseases, and cryptosporidiosis. We also discuss challenges and research priorities to accelerate discovery and development of urgently needed novel antiparasitic drugs.     

以生物合成为基础的代谢工程和组合生物合成

代谢工程和组合生物合成在筛选和发展新型药物方面日益成为生物、化学和医药界关注的重点。基于聚酮和聚肽类天然产物的独特化学结构和良好生物活性,研究它们的生物合成机制,将为合理化遗传修饰生物合成途径获得结构类似物提供遗传和生物化学的基础,实现利用现代生物学和化学的技术手段在微生物体内进行药物开发的目的。     

Selection of bead‐displayed,PNA‐encoded chemicals

The lack of efficient identification and isolation methods for specific molecular binders has fundamentally limited drug discovery. Here, we have developed a method to select peptide nucleic acid (PNA) encoded molecules with specific functional properties from combinatorially generated libraries. This method consists of three essential stages: (1) creation of a Lab‐on‐Bead? library, a one‐bead, one‐sequence library that, in turn, displays a library of candidate molecules, (2) fluorescence microscopy‐aided identification of single target‐bound beads and the extraction – wet or dry – of these beads and their attached candidate molecules by a micropipette manipulator, and (3) identification of the target‐binding candidate molecules via amplification and sequencing. This novel integration of techniques harnesses the sensitivity of DNA detection methods and the multiplexed and miniaturized nature of molecule screening to efficiently select and identify target‐binding molecules from large nucleic acid encoded chemical libraries. Beyond its potential to accelerate assays currently used for the discovery of new drug candidates, its simple bead‐based design allows for easy screening over a variety of prepared surfaces that can extend this technique's application to the discovery of diagnostic reagents and disease markers. Copyright © 2009 John Wiley & Sons, Ltd.     

天然活性成分作用靶点识别及确证方法的研究进展

药物靶标的发现和验证是新药研发的关键环节,对新药创制具有源头创新意义。天然产物是新药创制的重要来源,识别其作用靶点不仅为临床预防治疗提供可能新策略,也为进一步阐释中草药及其复方的作用特点及分子机制提供参考依据。随着生命科学和信息学的发展,药物靶点的识别及确证方法不断涌现,生物信息学、网络药理学、蛋白质组学、亲和色谱、药物亲和稳定性、芯片技术、基因敲除技术、RNA干扰等技术的广泛应用,越来越多的天然活性成分的靶点得以识别和验证。因此,本文对近五年来天然活性成分作用靶点识别及确证方法做一简要综述,以供参考。     

Screening for transient biological interactions as applied to albumin ligands: a new concept for drug discovery

The notion that many biological interactions are based on transient binding (dissociation constants (K(d)) in the range of 10-0.01 mM) is familiar, yet the implications for biological sciences have been realized only recently. An important area of biological sciences is drug design, where the traditional "lock and key" view of binding has prevailed and drug candidates are usually selected on their merits as being tight binders. However, the rationale that transient interactions are of importance for drug discovery is slowly gaining acceptance. These interactions may relate not only to the desired target interaction but also to unwanted interactions creating, for example, toxicity problems. Here we demonstrate, in a high-throughput screening format, affinity selection of weak binders to a model target of albumin by zonal retardation chromatography. It is perceived that this approach can define the "transient drug" as a complement to current drug discovery procedures.     

Reappraising a decade old explanatory model for pharmacognosy

It has been a decade since a tripod model of pharmacognosy – organism, biological activity, chemical structure – was proposed. Since then advances in all disciplines have taken science into the 21st century. What are the implications for pharmacognosy? In this paper we expand the previous model, adding a new module with focus on informatics to encompass results of new technical and theoretical advancements for drug discovery.     

Chemical language models for de novo drug design: Challenges and opportunities

Generative deep learning is accelerating de novo drug design, by allowing the generation of molecules with desired properties on demand. Chemical language models – which generate new molecules in the form of strings using deep learning – have been particularly successful in this endeavour. Thanks to advances in natural language processing methods and interdisciplinary collaborations, chemical language models are expected to become increasingly relevant in drug discovery. This minireview provides an overview of the current state-of-the-art of chemical language models for de novo design, and analyses current limitations, challenges, and advantages. Finally, a perspective on future opportunities is provided.     

Metabolomics for phytomedicine research and drug development

Metabolomics, including both targeted and global metabolite profiling strategies, is fast becoming the approach of choice across a broad range of sciences including systems biology, drug discovery, molecular and cell biology, and other medical and agricultural sciences. New analytical and bioinformatics technologies and techniques are continually being created or optimized, significantly increasing the crossdisciplinary capabilities of this new biology. The metabolomes of medicinal plants are particularly a valuable natural resource for the evidence-based development of new phytotherapeutics and nutraceuticals. Comparative metabolomics platforms are evolving into novel technologies for monitoring disease development, drug metabolism, and chemical toxicology. An efficient multidisciplinary marriage of these emerging metabolomics techniques with agricultural biotechnology will greatly benefit both basic and applied medical research.     

Genomic medicine: bringing biomarkers to clinical medicine

An important by-product of sequencing the human genome has been the development of a novel 'toolbox' for biomarker discovery and development. Genomic medicine is an emerging discipline in the genome sciences that integrates these tools to interrogate genomic variation in well-defined populations in order to develop predictors of disease susceptibility, progression and drug response. Several important classes of biomarkers result from these analyses which, when translated to clinical medicine and drug development, will have an important impact on human health and disease. This review highlights both the opportunities and challenges in bringing biomarkers into clinical medicine.     

From a Parkinson's disease expert: Rasagiline and the Future of Therapy

John Finberg is a professor of pharmacology at the Faculty of Medicine, Technion – Israel Institute of Technology, home of Israel's two Nobel laureates. He and his colleague Prof. Moussa Youdim were instrumental in the early clinical development of the anti-Parkinson drug rasagiline, which gained UK- and EU-marketing authorization in 2005 and US FDA approval in 2006. In our interview, Finberg reflects on his clinical research to develop rasagiline as a commercial drug and its proposed pharmacological mechanisms of action. Moreover, he elucidates the current state of anti-Parkinson drug discovery and offers direction for future research.     

From genes to therapeutics: educating the government and the public on biomedical sciences-a Singapore experience

Singapore has a highly developed economy and has been recognized to have one of the best business environments in Asia. Her success is based largely on focused developments of key industries in traded services and manufacturing sectors. The challenge for Singapore is to utilize her small human resource to transform the present economy to a more knowledge-intensive economy. Singapore has recently embarked on the ambitious goal of developing Biomedical Sciences as an industry. Educating the government and the public on various aspects of this new industry was identified as one of the essential steps towards this goal. The challenge was to inspire non-biologists to embrace the life sciences. This review describes how a series of workshops were developed to address the needs and the challenges of educating the public and the government.     

Chemical signals driving bacterial–fungal interactions

Microorganisms reside in diverse environmental communities where interactions become indispensable due to close physical associations. These interactions are driven by chemical communication among different microbial kingdoms, particularly between fungi and bacteria. Knowledge about these communication signals provides useful information about the nature of microbial interactions and allows predictions of community development in diverse environments. Here, we provide an update on the role of small signalling molecules in fungal–bacterial interactions with focus on agricultural and medicinal environments. This review highlights the range of – and response to – diverse biochemicals produced by both kingdoms with view to harnessing their properties towards drug discovery applications.     

Playing dice with mice: building experimental futures in Singapore

This short paper adds to debates on the unfolding spaces and logics of biotechnological development bought together in the 2009 special issue of New Genetics and Society on ‘Biopolitics in Asia’. Though an unlikely comparison between the development of the genomic sciences and the building of gambling casinos in the city state of Singapore, it reflects on the nature of political and technological investments in this South-East Asian city. It argues that Western expectations of a link between scientific practices, and civic epistemologies linked to democratic decision-making, are replaced by a rather different future orientation to scientific experimentation, economic investment and social development in Singapore.     

Learning developmental biology has priority in the life sciences curriculum in Singapore

Singapore has embraced the life sciences as an important discipline to be emphasized in schools and universities. This is part of the nation's strategic move towards a knowledge-based economy, with the life sciences poised as a new engine for economic growth. In the life sciences, the area of developmental biology is of prime interest, since it is not just intriguing for students to know how a single cell can give rise to a complex, coordinated, functional life that is multicellular and multifaceted, but more importantly, there is much in developmental biology that can have biomedical implications. At different levels in the Singapore educational system, students are exposed to various aspects of developmental biology. The author has given many guest lectures to secondary (ages 12-16) and high school (ages 17-18) students to enthuse them about topics such as embryo cloning and stem cell biology. At the university level, some selected topics in developmental biology are part of a broader course which caters for students not majoring in the life sciences, so that they will learn to comprehend how development takes place and the significance of the knowledge and impacts of the technologies derived in the field. For students majoring in the life sciences, the subject is taught progressively in years two and three, so that students will gain specialist knowledge in developmental biology. As they learn, students are exposed to concepts, principles and mechanisms that underlie development. Different model organisms are studied to demonstrate the rapid advances in this field and to show the interconnectivity of developmental themes among living things. The course inevitably touches on life and death matters, and the social and ethical implications of recent technologies which enable scientists to manipulate life are discussed accordingly, either in class, in a discussion forum, or through essay writing.     

Discovery of antichagasic inhibitors by high-throughput screening with Trypanosoma cruzi glucokinase

A high-throughput screening (HTS) campaign was carried out for Trypanosoma cruzi glucokinase (TcGlcK), a potential drug-target of the pathogenic protozoan parasite. Glycolysis and the pentose phosphate pathway (PPP) are important metabolic pathways for T. cruzi and the inhibition of the glucose kinases (i.e. glucokinase and hexokinase) may be a strategic approach for drug discovery. Glucose kinases phosphorylate d-glucose with co-substrate ATP to yield G6P, and moreover, the produced G6P enters both pathways for catabolism. The TcGlcK – HTS campaign revealed 25 novel enzyme inhibitors that were distributed in nine chemical classes and were discovered from a primary screen of 13,040 compounds. Thirteen of these compounds were found to have low micromolar IC₅₀ enzyme – inhibition values; strikingly, four of those compounds exhibited low toxicity towards NIH-3T3 murine host cells and notable in vitro trypanocidal activity. These compounds were of three chemical classes: (a) the 3-nitro-2-phenyl-2H-chromene scaffold, (b) the N-phenyl-benzenesulfonamide scaffold, and (c) the gossypol scaffold. Two compounds from the 3-nitro-2-phenyl-2H-chromene scaffold were determined to be hit-to-lead candidates that can proceed further down the early-stage drug discovery process.     

系统生物学对医学的影响

系统生物学是21世纪最前沿的科学之一,它是随着生命科学飞速发展而产生的一门新兴生物学分支[1],它综合数学、信息科学和生物学的各种工具来阐明和理解大量的数据所包含的生物医学意义,从而使人们能够从整体上理解生物医学系统并精确、量化地预测生物医学系统的行为。随着系统生物学的发展及其理论的突破,将在疾病诊治、新药开发、预防医学方面发挥重要的作用,有助于弥补传统医学缺陷并促进其发展。     

Biotec Visions September 2009

News: Fighting iron deficiency – Measuring cellular forces – Better photobioreactor design for hydrogen production – Artificial nerve cell – After GFP: Infrared IFP – Predictable transfection – RNAi for improved protein production – 3D protein map – Self-irrigating rhubarb – Cool plasma to fight biofilms – Pus elasticity – Plants surviving the frost Special Issues: Imaging host-pathogen interactions – Plant in vitro technologies – Biodiesel WIREs Nanomedicine and Nanobiotechnology: Drug-eluting stent coatings – Particle fabrication for diagnostic imaging and drug delivery Encyclopaedia of Life Sciences: Antiprotozoan drugs – Autoimmune disease: Treatment Opinion: A Korean vision on Green Growth Most Read Metagenomics Tips and Tricks: Increase your protein solubility – Printing viable cells Writing tips: The title impact In short: Cell cloning in micropallet array – Bioprocesses for air pollution control – Cells surviving the frost – Oil spilling onto seafloor sediments Test your Knowledge Briefs