Using Drosophila models of neurodegenerative diseases for drug discovery

Introduction: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are increasing in prevalence as our aging population increases in size. Despite this, currently there are no disease-modifying drugs available for the treatment of these conditions. Drosophila melanogaster is a highly tractable model organism that has been successfully used to emulate various aspects of these diseases in vivo. These Drosophila models have not been fully exploited in drug discovery and design strategies.

Areas covered: This review explores how Drosophila models can be used to facilitate drug discovery. Specifically, we review their uses as a physiologically-relevant medium to high-throughput screening tool for the identification of therapeutic compounds and discuss how they can aid drug discovery by highlighting disease mechanisms that may serve as druggable targets in the future. The reader will appreciate how the various attributes of Drosophila make it an unsurpassed model organism and how Drosophila models of neurodegeneration can contribute to drug discovery in a variety of ways.

Expert opinion: Drosophila models of human neurodegenerative diseases can make a significant contribution to the unmet need of disease-modifying therapeutic intervention for the treatment of these increasingly common neurodegenerative conditions.     

Invertebrate and fungal model organisms: emerging platforms for drug discovery

Early-stage translational research programs have increasingly exploited yeast, worms and flies to model human disease. These genetically tractable organisms represent flexible platforms for small molecule and drug target discovery. This review highlights recent examples of how model organisms are integrated into chemical genomic approaches to drug discovery with an emphasis on fungal yeast, nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster. The roles of these organisms are expanding as novel models of human disease are developed and novel high-throughput screening technologies are created and adapted for drug discovery.     

The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update

Introduction: The exponential growth in the world's aged population has increased pressure on drug discovery efforts to identify innovative therapies for Alzheimer's disease (AD). The long and uncertain clinical trial path utilized to test the potential efficacy of these novel agents is challenging. For these and other reasons, there has been an explosion in the generation and availability of transgenic mouse models that mimic some, but not all aspects of AD. The largely overwhelmingly positive results obtained when testing potential clinical agents in these same animal models have failed to translate into similar positive clinical outcomes.

Areas covered: This review discusses the value and limitations associated with currently available transgenic mouse models of AD. Furthermore, the article proposes ways in which researchers can better characterize pharmacodynamic and pharmacokinetic endpoints to increase the success rate for novel therapies advancing into clinical development. Lastly, the author discusses ways in which researchers can supplement, expand and improve transgenic mouse models used in AD drug discovery.

Expert opinion: The use of transgenic mouse models that recapitulate various aspects of AD has expanded our knowledge and understanding of disease pathogenesis immensely. Further success in testing and translating novel therapies from animal models into bona fide medicines would be enhanced by i) the availability of better models that more fully recapitulate the disease spectrum, ii) defining and measuring standardized endpoints that display a pharmacodynamic range, iii) building and including translatable biomarkers and iv) including novel endpoints that would be expected to translate into clinically beneficial outcomes.     

Gene expression profiling and therapeutic interventions in neurodegenerative diseases: a comprehensive study on potentiality and limits

Introduction: Neurodegenerative diseases are incurable debilitating disorders of the nervous system that affect approximately 30 million people worldwide. Despite profuse efforts attempting to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. The novelty of their mechanisms represents a challenge to biology, to their related biomarkers identification and drug discovery. Because of their multifactorial aspects and complexity, gene expression analysis platforms have been extensively used to investigate altered pathways during degeneration and to identify potential biomarkers and drug targets.

Areas covered: This work offers an overview of the gene expression profiling studies carried out on Alzheimer's disease, Huntington's disease, Parkinson's disease and prion disease specimens. Therapeutic approaches are also discussed.

Expert opinion: Although many therapeutic approaches have been tested, some of them acting on several altered cellular pathways, no effective cures for these neurodegenerative diseases have been identified. Microarray technology must be associated with functional proteomics and physiology in an effort to identify specific and selective biomarkers and druggable targets, thus allowing the successful discovery of disease-modifying therapeutic treatments.     

Simple animal models for amyotrophic lateral sclerosis drug discovery

ABSTRACT

Introduction: Simple animal models have enabled great progress in uncovering the disease mechanisms of amyotrophic lateral sclerosis (ALS) and are helping in the selection of therapeutic compounds through chemical genetic approaches.

Areas covered: Within this article, the authors provide a concise overview of simple model organisms, C. elegans, Drosophila and zebrafish, which have been employed to study ALS and discuss their value to ALS drug discovery. In particular, the authors focus on innovative chemical screens that have established simple organisms as important models for ALS drug discovery.

Expert opinion: There are several advantages of using simple animal model organisms to accelerate drug discovery for ALS. It is the authors’ particular belief that the amenability of simple animal models to various genetic manipulations, the availability of a wide range of transgenic strains for labelling motoneurons and other cell types, combined with live imaging and chemical screens should allow for new detailed studies elucidating early pathological processes in ALS and subsequent drug and target discovery.     

Non-mammalian animal models of Parkinson's disease for drug discovery

Importance of the field: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of predominantly elderly individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. Compounding this problem is the current lack of a truly representative mammalian model of PD. However, a number of non-mammalian models of PD have been created in recent years that hold tremendous promise to accelerate our understanding of the disease as well as to transform the drug discovery process.

Areas covered in this review: This review provides an overview of the various Caenorhabditis elegans and Drosophila genetic models of PD that have been generated to date and discusses the utility of these model systems in the identification of molecules of potential therapeutic value for the PD patient.

What the reader will gain: Readers will appreciate the strengths (and limitations) of C. elegans and Drosophila in modeling salient features of the disease as well as their usefulness in uncovering novel gene–gene interaction and pathways relevant to PD pathogenesis. Readers will also appreciate how technological advancements have allowed the direct evaluation of novel compounds in these living models of PD in a virtually high-throughput manner.

Take home message: Non-mammalian models of PD provide a valuable in vivo platform for drug screening. Unlike cell-based systems, these living models with an intact nervous system allow for a more meaningful evaluation of the neuroprotective properties of genetic and chemical modifiers to be conducted.     

Advances in the identification of β-secretase inhibitors

Introduction: Alzheimer's disease (AD), which is characterized by progressive intellectual deterioration, is the most common cause of dementia. β-Secretase (or BACE1) expression is a trigger for amyloid β peptide formation, a cause of AD, and thus is a molecular target for the development of drugs against AD. Many BACE1 inhibitors have been identified by academic and pharmaceutical research groups and a number of advanced technologies in drug discovery have been applied to the drug discovery.

Areas covered: The purpose of this review is to present and discuss the methodologies used for BACE1 inhibitor drug discovery via substrate- and structure-based design, high-throughput screening and fragment-based drug design. The authors also review the advantages and disadvantages of these methodologies.

Expert opinion: Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.     

QSAR methods for the discovery of new inflammatory bowel disease drugs

Introduction: Inflammatory bowel disease (IBD) represents an important class of chronic gastrointestinal tract disease. And although there are already several useful treatments to reduce and control the symptoms, there is still no cure. One drug discovery technique used is the computer-aided (in silico) discovery approach which has largely demonstrated efficacy. Computational techniques, when used in combination with traditional drug discovery methodology, greatly increase the chance of drug discovery in a sustainable and economical fashion.

Areas covered: This review aims to provide the most recent and important advances of in silico IBD drug discovery. While this review is mainly focused on QSAR methods, especially those based on molecular topology (MT), additional topics, such as docking or comparative field analysis are also addressed.

Expert opinion: IBD is a worldwide growing health concern that can only be currently treated in symptomatic and palliative way; thus, the search for new drugs is imperative. Computer-aided methods, which focus on the drug–receptor interaction, are essential tool in this regard. It is noted, however that a major problem is that although there are many known receptors associated with IBD, none of these have yet been found essential. The use of other approaches, including QSAR methodology, is certainly a complementary and attractive alternative; especially QSAR methods based on MT, which has proven successful in other drug discovery.     

Identification of drug candidates and repurposing opportunities through compound–target interaction networks

Introduction: System-wide identification of both on- and off-targets of chemical probes provides improved understanding of their therapeutic potential and possible adverse effects, thereby accelerating and de-risking drug discovery process. Given the high costs of experimental profiling of the complete target space of drug-like compounds, computational models offer systematic means for guiding these mapping efforts. These models suggest the most potent interactions for further experimental or pre-clinical evaluation both in cell line models and in patient-derived material.

Areas covered: The authors focus here on network-based machine learning models and their use in the prediction of novel compound–target interactions both in target-based and phenotype-based drug discovery applications. While currently being used mainly in complementing the experimentally mapped compound–target networks for drug repurposing applications, such as extending the target space of already approved drugs, these network pharmacology approaches may also suggest completely unexpected and novel investigational probes for drug development.

Expert opinion: Although the studies reviewed here have already demonstrated that network-centric modeling approaches have the potential to identify candidate compounds and selective targets in disease networks, many challenges still remain. In particular, these challenges include how to incorporate the cellular context and genetic background into the disease networks to enable more stratified and selective target predictions, as well as how to make the prediction models more realistic for the practical drug discovery and therapeutic applications.     

Xenograft and genetically engineered mouse model systems of osteosarcoma and Ewing's sarcoma: tumor models for cancer drug discovery

Introduction: There are > 75 histological types of solid tumors that are classified into two major groups: bone and soft-tissue sarcomas. These diseases are more prevalent in children, and pediatric sarcomas tend to be highly aggressive and rapidly progressive. Sarcomas in adults may follow a more indolent course, but aggressive tumors are also common. Sarcomas that are metastatic at diagnosis, or recurrent following therapy, remain refractory to current treatment options with dismal overall survival rates. A major focus of clinical trials, for patients with sarcoma, is to identify novel and more effective therapeutic strategies targeted to genomic or proteomic aberrations specific to the malignant cells. Critical to the understanding of the potential for targeted therapies are models of disease that are representative of clinical disease and predictive of relevant clinical responses.

Areas covered: In this article, the authors discuss the use of mouse xenograft models and genetically engineered mice in cancer drug discovery. The authors provide a special focus on models for the two most common bone sarcomas: osteosarcoma (OS) and Ewing's sarcoma (ES).

Expert opinion: Predicting whether a new anticancer agent will have a positive therapeutic index in patients with OS and ES remains a challenge. The use of mouse sarcoma models for understanding the mechanisms involved in the response of tumors to new treatments is an important step in the process of drug discovery and the development of clinically relevant therapeutic strategies for these diseases.     

Invertebrate disease models in neurotherapeutic discovery

Models that reproduce many of the cellular and molecular aspects of various human neurodegenerative disorders have been developed in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans. An understanding of the underlying molecular and genetic mechanisms of disease pathogenesis is being gained from studies utilizing the wealth of genetic and molecular tools available for these invertebrate model organisms. This review focuses on recent studies that lay a foundation for utilizing these disease models in drug discovery and for continued genetic dissection of disease mechanisms.     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

基于网络药理学研究当归芍药散防治阿尔茨海默病的作用机制

目的 探究当归芍药散防治阿尔茨海默病的作用机制。方法 选取当归芍药散中的当归、白芍、白术、川芎、茯苓、泽泻为研究对象,应用TCMSP数据库对6味中药主要化学成分进行筛选;使用TCMSP数据库,对筛选出的化合物及阿尔茨海默病进行靶点预测,选取当归芍药散与阿茨海默病一致的6个靶点蛋白作为后续研究对象,通过生物分子功能注释系统（MAS 3.0）及KEGG通路数据库进行通路注解及分析,得到当归芍药散治疗阿茨海默病的相关靶点通路预测图及相关信号通路。结果 从当归芍药散中筛选出35个化合物,可作用于阿尔茨海默病6个潜在的蛋白靶点,找出靶点的相关通路22条。作用通路涉及阿尔茨海默病发病机制相关的钙信号途径、炎症、免疫调节、细胞与细胞之间的信号交流、肌动蛋白细胞骨架的调节等各个环节,6味中药既有共同的成分及作用靶点、通路,又各有偏重,各通路间通过共有靶点连接,显示出不同成分间的多靶点、多途径的协同作用。结论 预测出当归芍药散治疗阿尔茨海默病可能与其调节炎症、免疫系统、钙信号、细胞与细胞之间的信号交流等机制有关。     

The concept of privileged structures in rational drug design: focus on acridine and quinoline scaffolds in neurodegenerative and protozoan diseases

Introduction: For nearly 20 years, privileged structures have offered an optimal source of core scaffolds and capping fragments for the design of combinatorial libraries directed at a broad spectrum of targets. From describing structures promiscuous within a given target family, the concept has evolved to include frameworks that can modulate proteins lacking a strict target class relation.

Areas covered: Based on a literature search from 2000 to 2010, we discuss how two privileged motifs, quinolines and acridines, are particularly recurrent in compounds active against two quite different pathologies, neurodegenerative and protozoan diseases.

Expert opinion: As privileged structures, quinolines and acridines could improve the productivity of drug discovery projects in the field of neurodegenerative and protozoan diseases. They could be particularly relevant for protozoan diseases because of the importance of cost-effective strategies and less stringent intellectual property concerns. Furthermore, because of their inherent affinity for various targets, privileged structures could offer a viable starting point in the search for novel multi-target ligands. Finally, from a broader perspective, they can serve as effective probes for investigating unknown but interrelated mechanisms of action.     

An assessment of the translational relevance of Drosophila in drug discovery

Introduction: Drosophila melanogaster offers a powerful expedient and economical system with facile genetics. Because of the high sequence and functional conservation with human disease-associated genes, it has been cardinal in deciphering disease mechanisms at the genetic and molecular level. Drosophila are amenable to and respond well to pharmaceutical treatment which coupled to their genetic tractability has led to discovery, repositioning, and validation of a number of compounds.

Areas covered: This review summarizes the generation of fly models of human diseases, their advantages and use in elucidation of human disease mechanisms. Representative studies provide examples of the utility of this system in modeling diseases and the discovery, repositioning and testing on pharmaceuticals to ameliorate them.

Expert opinion: Drosophila offers a facile and economical whole animal system with many homologous organs to humans, high functional conservation and established methods of generating and validating human disease models. Nevertheless, it remains relatively underused as a drug discovery tool probably because its relevance to mammalian systems remains under question. However, recent exciting success stories using Drosophila disease models for drug screening, repositioning and validation strongly suggest that fly models should figure prominently in the drug discovery pipeline from bench to bedside.     

New non-oral drug delivery systems for Parkinson's disease treatment

Introduction: Parkinson's disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, but still unmet needs regarding its long-term management. Levodopa (LD) remains the most effective treatment; however, chronic use is associated with potentially disabling motor complications.

Areas covered: This review highlights a variety of new non-oral drug delivery strategies for non-invasive and invasive routes of drug administration for the treatment of PD. It also includes current and future trends of liposomes, solid lipid nanoparticles and biocompatible microparticles as new non-oral drug delivery systems.

Expert opinion: The long-term complications and limitations of LD treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with a new non-oral drug delivery system, with the aim of achieving long-lasting and less fluctuating drug levels, minimization of peak levels and thereby reduction of side effects.     

Current perspectives on pharmacotherapy of Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials .

Areas covered: This review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years.

Expert opinion: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.