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.     

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.     

Focusing on new monoamine oxidase inhibitors

Importance of the field: Monoamine oxidase (MAO) plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. Furthermore, modulators of neurotransmitters exert pleiotropic effects on mental and cognitive functions. The by-products of MAO-mediated reactions include several chemical species with neurotoxic potential. It is widely speculated that prolonged or excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of human MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders.

Areas covered in this review: This review highlights the recent MAO inhibitors related patents published from July 2005 to December 2009. It also reports on new associations of already known MAO inhibitors with other drugs, innovative therapeutic targets, MAO inhibitors obtained by plants extraction, alternative administration routes and synthetic processes.

What the reader will gain: The reader will gain an overview of the main structures being investigated and their biological activities.

Take home message: Several of these MAO inhibitors appear promising for further clinical development.     

Bruton's tyrosine kinase as a molecular target in treatment of leukemias and lymphomas as well as inflammatory disorders and autoimmunity

Importance of the field: Bruton's tyrosine kinase (BTK) has emerged as a new anti-apoptotic molecular target for the treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that BTK inhibitors may be useful in the treatment of leukemias and lymphomas. BTK inhibitors may also be helpful in prevention and treatment of thromboembolic complications as well as inflammatory disorders.

Areas covered in this review: We provide a comprehensive review of the target diseases for which the use of BTK inhibitors may be helpful as well as the activity profiles of BTK inhibitors.

What the reader will gain: We review the currently available translational research, biomarker as well as patent literature regarding BTK molecular target and BTK inhibitors.

Take home message: BTK inhibitors may provide the foundation for therapeutic innovation against B-lineage leukemias/lymphomas, inflammatory disorders and autoimmunity.     

Glycosidase inhibitors: a patent review (2008 – 2013)

Introduction: In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a key role in many biological processes. The importance of these enzymes is also reflected by a number of diseases, which result from the lack or dysfunction of a given glycosidase, as well as by the use of glycosidase inhibitors in the treatment of metabolic disorders or viral infections. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, carbasugars, thiosugars and other non-glycosidic compounds will be discussed and special attention will be given to the ones that are currently used clinically.

Areas covered: This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the relevant research, patents and patent applications filed in the past years on the field.

Expert opinion: Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research toward developing new generations of these molecules is very important to public health in the world. The unique combination of these compounds – for example, they share many properties with natural carbohydrates and also possess distinct specific characteristics – makes them precious for pharmaceutical companies in an attempt to search for potential new drugs. Currently, the most promising compounds are the iminosugars and thiosugars due to their better oral bioavailability.     

Potential of transglutaminase 2 as a therapeutic target

Importance of the field: Increased expression and activity of transglutaminase 2 – a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues – are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases.

Areas covered in this review: The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases.

What the reader will gain: Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment.

Take home message: New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.     

Curcumin and neurodegenerative diseases: a perspective

Introduction: Curcumin, a dietary polyphenol found in the curry spice turmeric, possesses potent antioxidant and anti-inflammatory properties and an ability to modulate multiple targets implicated in the pathogenesis of chronic illness. Curcumin has shown therapeutic potential for neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD).

Areas covered: This article highlights the background and epidemiological evidence of curcumin's health benefits and its pharmacodynamic and pharmacokinetic profile. Curcumin's ability to counteract oxidative stress and inflammation and its capacity to modulate several molecular targets is reviewed. We highlight the neuroprotective properties of curcumin including pre-clinical evidence for its pharmacological effects in experimental models of AD and PD. The bioavailability and safety of curcumin, the development of semi-synthetic curcuminoids as well as novel formulations of curcumin are addressed.

Expert opinion: Curcumin possesses therapeutic potential in the amelioration of a host of neurodegenerative ailments as evidenced by its antioxidant, anti-inflammatory and anti-protein aggregation effects. However, issues such as limited bioavailability and a paucity of clinical studies examining its therapeutic effectiveness in illnesses such as AD and PD currently limit its therapeutic outreach. Considerable effort will be required to adapt curcumin as a neuroprotective agent to be used in the treatment of AD, PD and other neurodegenerative diseases.     

Therapeutic potential of Panax ginseng and its constituents,ginsenosides and gintonin,in neurological and neurodegenerative disorders: a patent review

Introduction: Ginseng, Panax ginseng, has been used for various diseases and proven its great efficacy in managing central nervous system diseases.

Area covered: This article covers the therapeutic potential of patents on ginseng and its active constituents to develop therapies for neurodegenerative and neurological disorders, since 2010. The literature review was provided using multiple search engines including Google Patent, Espacenet and US Patent in the field of neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, cognitive, and neurological disorders.

Expert opinion: The gathered data represented outstanding merits of ginseng in treatment of neurodegenerative and neurological disorders. These effects have been mediated by neurogenesis, anti-apoptotic and antioxidant properties, inhibition of mitochondrial dysfunction, receptor-operated Ca²⁺ channels, amyloid beta aggregation, and microglial activation as well as neurotransmitters modulation. However, these compounds have limited clinical application of for the prevention or treatment of neurodegenerative and neurological disorders. This might be due to incomplete data on their clinical pharmacokinetic and toxicity properties, and limited economic investments. There is an increasing trend in use of herbal medicines instead of chemical drugs, so it is time to make more attention to the application of ginseng, the grandfather of medicinal plants, from basic sciences to patients’ bed.     

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

Introduction: Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylates more than one hundred different sequences within proteins in a variety of different pathways. It is a key component of a remarkably large number of cellular processes and diseases. Imbalance of GSK-3 activity is involved in various prevalent pathological diseases, such as diabetes, neurodegenerative diseases and cancer. Understanding its role in different disorders has been central in the last several decades and there has been a significantly large development of GSK-3 inhibitors, some of which, show promising results for the treatment of these devastating diseases.

Areas covered: This review covers patent literature on GSK-3 inhibitors and their applications published and/or granted between 2014 and 2015.

Expert opinion: GSK-3 inhibitors have gained a prominent role in regenerative medicine based in their ability to modulate stem cells. Moreover, some allosteric modulators of GSK-3 emerge as safe compounds for chronic treatments.     

Inhibitors of cathepsin C (dipeptidyl peptidase I)

Importance to the field: Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis.

Areas covered in this review: Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 – 2009).

What the reader will gain: It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors.

Take home message: All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.     

Safinamide in the treatment of Parkinson's disease

Importance of the field: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage.

Areas covered in this review: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound – safinamide, which has both dopaminergic and non-dopaminergic actions – might address these.

What the reader will gain: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced ‘OFF’ time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD.

Take home message: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.     

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.     

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.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.     

Novel monoamine oxidase inhibitors: a patent review (2012 – 2014)

Introduction: Monoamine oxidase (MAO) inhibitors, despite the initial pharmacological interest, are used in clinic for their antidepressant effect and in the management of Parkinson symptoms, due to the established neuroprotective action. Efficacy and tolerability emerged from large-scale and randomized clinical trials.

Areas covered: Thirty-six patents range from April 2012 to September 2014. The number of chemotypes with inhibitory effects on MAO is truly high (40 synthetic compounds, 22 natural products and 6 plant extracts reported and licensed), and the present review is comprehensive of all compounds, which have been patented for their relevance to clinical medicine in this period range (27 patents). Moreover, some of the collected patents deal with new formulations of compounds endowed with MAO inhibitory properties (two patents) and new therapeutic options/drug associations for already known MAO inhibitors (seven patents).

Expert opinion: The patents reported in this review showed that the interest in this field is constant and mainly devoted to the study of selective MAO-B inhibitors, used as drugs for the treatment of neurological disorders. The development of novel human MAO inhibitors took advantage of the discovery of new therapeutic targets (cancer, hair loss, muscle dystrophies, cocaine addiction and inflammation), the recognized role of MAOs as molecular biomarkers and their activity in other tissues.     

A review of compliance to treatment in Alzheimer's disease: potential benefits of a transdermal patch

ABSTRACT

Background: Following prescribed medication regimens is essential for the effective treatment of any medical condition. Unfortunately, patients often fail to follow recommendations, and treatment non-compliance represents a widespread, often underestimated problem, placing tremendous burden on the healthcare system. Compliance in Alzheimer's disease (AD), a chronic neurodegenerative disease typically afflicting older adults, is especially challenging.

Scope: To review factors contributing to poor treatment compliance in AD, considering the prominent role care­givers often play in treatment management; and acknowledging strategic approaches, particularly modern transdermal patches, to improve compliance in this particularly susceptible population. Articles were identified by searching MEDLINE in November 2006 (search limits: 1987–2007) using the terms: compliance; Alzheimer's; treatment; and transdermal. Additional resources included bibliographies of identified articles.

Findings: Strategic approaches to improving treatment compliance include: simplifying treatment regimens, using reminder packaging, and developing more patient- or caregiver-friendly modes of administration. To date, AD therapies have been administered orally. However, recent developments in alternative modes of drug delivery, such as transdermal patches, may offer effective, well-tolerated treatment options with the potential to enhance compliance. A patch containing rivastigmine (Exelon*), an established cholinesterase inhibitor, has been developed and demonstrated to have good efficacy and tolerability in patients with AD. In addition, initial caregiver experience suggests preference for the patch over oral administration.

Conclusion: Transdermal patches may be an effective way to optimize treatment compliance for AD, as well as an increasing number of other chronic conditions that typically afflict the older population, offering the possibility of more sustained clinical benefits.     

Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila

Introduction: Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms.

Areas covered: The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models.

Expert opinion: Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.     

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.     

SHIP2 and its involvement in various diseases

Importance of the field: Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. The functional upregulation of SHIP2 results in signaling blockade, leading to related disorders.

Areas covered in this review: We first summarize the role of SHIP2 in the regulation of insulin signaling and type 2 diabetes, including remarkable advances in pharmacological approaches. In addition, this review highlights new findings regarding the involvement of SHIP2 in a number of diseases, including cancer, neurodegenerative diseases, and atherosclerosis.

What the reader will gain: Recently identified small-molecule inhibitors of SHIP2 phosphatase activity emphasize the potential therapeutic value of SHIP2. In addition, currently available evidence demonstrates the importance of the scaffolding-type protein function of SHIP2. Understanding this interesting function will help clarify the complicated involvement of SHIP2 in various disorders.

Take home message: Recent studies have demonstrated that SHIP2 is a promising therapeutic target for not only type 2 diabetes, but also cancer, neurodegenerative diseases, and atherosclerosis. Targeting SHIP2 through specific small-molecule inhibitors will have beneficial effects on these diseases.