The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this (...) exogenous, inhibitory, L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

Computational drug repositioning has been proven as a promising and efficient strategy for discovering new uses from existing drugs. To achieve this goal, a number of computational methods have been proposed, which are based on different data sources of drugs and diseases. These methods approach the problem using either machine learning- or network-based models with an assumption that similar drugs can be used for similar diseases to identify new indications of drugs. Therefore, similarities between drugs and between diseases are (...) usually used as inputs. In addition, known drug-disease associations are also needed for the methods as prior information. It should be noted that those associations are still not well established due to the fact that many of marketed drugs have been withdrawn and this could affect the outcome of the methods. In this study, we propose a novel method named RLSDR to find new uses of drugs. More specifically, it relies on a semi-supervised learning model, Regularized Least Square, thus it does not require definition of non-drug-disease associations as previously proposed machine learning-based methods. In addition, the similarity between drugs measured by chemical structures of drug compounds and the similarity between diseases which share phenotypes can be represented in a form of either similarity network or similarity matrix as inputs of the method. Moreover, instead of using a gold-standard set of known drug-disease associations, we construct an artificial set of the associations based on known disease-gene and drug-target associations. Experiment results demonstrate that RLSDR achieves better prediction performance on the artificial set of drug-disease associations than that on the gold-standard ones in terms of area under the Receiver Operating Characteristic curve. In addition, it outperforms two representative network-based methods irrespective of the prior information of drug-disease associations. Novel indications for a number of drugs are also identified and validated by evidences from a different data resource. (shrink)

In Gustavsson et al,1 we discussed the ethical issues that arise when identifying the relevant population for disease-modifying drugs targeting Alzheimer disease. More specifically, we focused on novel immunotherapies aimed at amyloid β and tau, two relevant biomarkers. The commentaries to our paper2 3 acknowledge our conclusion: screening for AD involve ethical costs that cannot be justified unless a drug with clinically relevant effect becomes available. Since Aduhelm is the only immunotherapy targeting AD currently approved by the Food and (...) Drug Administration, we use that as a …. (shrink)

Signaling complexes and networks are being intensely studied in an attempt to discover pathways that are amenable to therapeutic intervention. A challenge in this search is to understand the effect that the modulation of a target will have on the overall function of a cell and its surrounding neighbors. Protein‐interaction mapping reveals relationships between proteins and their impact on cellular processes and is being used more widely in our understanding of disease mechanisms and their treatment. The review discusses challenges and (...) breakthroughs in this new and evolving area and its impact on medicine. BioEssays 27:958–969, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The concept of a G‐quartet, a unique structural arrangement intrinsic to guanine‐rich DNA, was first introduced by Gellert and colleagues1 over 40 years ago. For decades, it has been uncertain whether the G‐quartet and the structure that it gives rise to, the G‐quadruplex, are purely in vitro phenomena. Nevertheless, the presence of signature G‐rich motifs in the eukaryotic genome, and the plethora of proteins that bind to, modify or resolve this nucleic acid structure in vitro have provided circumstantial evidence for (...) its physiological relevance. More recently, direct visualisation of G‐quadruplex DNA at native telomeres was achieved, bolstering the evidence for its existence in the cell. Furthermore, G‐quadruplex folded telomeric DNA has been found to perturb telomere function and to impede the action of telomerase, an enzyme overexpressed in >85% of human cancers, hence opening up a novel avenue for cancer therapy in the form of G‐quadruplex stabilising agents. BioEssays 29: 155–165, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Intensive research is carried out to develop a disease-modifying drug for Alzheimer’s disease. The development of drug candidates that reduce Aß or tau in the brain seems particularly promising. However, these drugs target people at risk for AD, who must be identified before they have any, or only moderate, symptoms associated with the disease. There are different strategies that may be used to identify these individuals. Each of these strategies raises different ethical challenges. In this paper, we analyse (...) these challenges in relation to the risk stratification for AD necessary for using these drugs. We conclude that the new drugs must generate large health benefits for people at risk of developing AD to justify the ethical costs associated with current risk stratification methods, benefits much larger than current drug candidates have. This conclusion raises a new set of ethical questions that should be further discussed. No data are available. (shrink)

Proteolysis-targeting chimeric molecules represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to (...) physiological substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. The hetero-bifunctional PROTAC molecules contain a ligand for recruiting an E3 ligase linked with a ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” disease-causing proteins, which are not limited to physiological substrates of the ubiquitin-protease system, suggesting great prospects for therapeutic development. (shrink)

The Alzheimer field is in desperate need for an effective treatment. After decades of research, the available drugs treat only symptoms, and even their effectiveness is disputed. Because brain changes precede the clinical symptoms by years to decades, disease-modifying treatments should probably be started early, when the first symptoms occur—or even before. But how to determine who to treat? In this issue, Erik Gustavsson c.s. approach this question by addressing the benefits, harms and ethical issues encountered when using different modes (...) of screening for ‘preclinical’ or early symptomatic Alzheimer disease.1 Their overall conclusion is clear—screening for high risk of developing AD dementia to select those who are eligible for treatment is ethically problematic, unless extremely effective treatment becomes available. An additional major challenge is that diagnostic test accuracy is generally poor, with a particularly high risk of false-positive results, that is, biological evidence of Alzheimer pathology in persons who will never develop dementia. The risk of overmedicalisation is serious, and the potential harms of screening for AD should not be ignored, as Le Couteur c.s. previously argued.2 In short, there is no evidence base for any form of screening for AD whether in a preclinical stage (an …. (shrink)

The article by Gustavsson et al 1 addresses the important question how to handle new medications with focus on drug candidates that reduce Aβ or tau in the brain, for individuals with Alzheimer’s disease, where the need for a disease-modifying drug is enormous. There are several ethical issues to deal with. The challenges and ethical implications associated with whom should be eligible for treatment are thoroughly discussed in the article. Should treatment only be available to those with mild (...) symptoms and/or to those with no symptoms but with risk for AD? Where do we draw the line between who will be eligible for treatment and who will not? Who will be responsible for the prioritisation? There are many ethical problems with both population screening and screening of those with high risk well discussed in the article. Indeed, the first immunotherapy drug Aducanumab was approved by the US Food and Drug Administration in …. (shrink)

A lack of transparency and concerns over patients costs at the pharmacy counter have increased Congressional focus on pharmacy benefits management practices. However, applying regulations without transparency into pharmacy benefits managers practices could do more harm than good.

Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only as a “necessary” prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of “drug instrumentalization.” Psychoactive drugs are consumed for their effects on mental states. Humans (...) are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific “instrumentalization goals” and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future. (shrink)

In this article C. L. Tsou, of the Institute of Biophysics, Beijing, criticizes the use of the expression I50, the inhibitor concentration to produce 50% inhibition of a particular enzyme as a ‘most unfortunate’ parameter, when screening enzyme inhibitors designed as drugs. Comments on Dr Tsou's point of view will be welcomed from readers.

The assessment of nanotechnology applications such as nanocarrier-based targeted drug delivery has historically been based mostly on toxicological and safety aspects. The use of nanocarriers for TDD, a leading-edge nanomedical application, has received little study from the angle of experts’ perceptions and acceptability, which may be reflected in how TDD applications are developed. In recent years, numerous authors have maintained that TDD assessment should also take into account impacts on ethical, environmental, economic, legal, and social issues in order to (...) lead to socially responsible innovation. Semi-structured interviews were conducted with French and Canadian researchers and research trainees with diverse disciplinary backgrounds and involved in research related to emerging technologies. The interviews focussed on scenarios presenting two types of TDD nanocarriers in two contexts of use. Content and inductive analyses of interviews showed how facets of perceived impacts such as health, environment, social cohabitation, economy, life and death, representations of the human being and nature, and technoscience were weighed in acceptability judgments. The analyses also revealed that contextual factors related to device, to use, and to user influenced the weighting assigned to perceived impacts and thus contributed to variability in interviewees’ judgments of acceptability. Giving consideration to researchers’ perspective could accompany first steps of implementation and development of nanomedicine by producing a first, but wide, picture of the acceptability of nanocarrier-based TDD. (shrink)

The simian virus 40 chromosome, a model for the mammalian replicon, is a uniquely powerful system for the study of drugs and treatments which target enzymes of the mammalian replication apparatus. High resolution gel electrophoretic analysis of normal and aberrant viral replication intermediates can be used effectively to understand the molecular events of replication failure. These events include breakage of replication forks, aberrant topoisomerase action, failure to separate daughter chromosomes, protein‐DNA crosslinking, single and double strand DNA breakage, alterations in topology (...) and inactivation of replication intermediates. The SV40 replication system can also be used to study the recombinational events which often follow drug‐induced replication failure. (shrink)

The promises of nanotechnology have been framed by a variety of metaphors, that not only channel the attention of the public, orient the questions asked by researchers, and convey epistemic choices closely linked to ethical preferences. In particular, the image of the ‘therapeutic missile’ commonly used to present targeted drug delivery devices emphasizes precision, control, surveillance and efficiency. Such values are highly praised in the current context of crisis of pharmaceutical innovation where military metaphors foster a general mobilization of (...) resources from multiple fields of cutting-edge research. The missile metaphor, reminiscent of Paul Ehrlich’s ‘magic bullet’, has framed the problem in simple terms: how to deliver the right dose in the right place at the right moment? Chemists, physicists and engineers who design multi-functional devices operating in vitro can think in such terms, as long as the devices are not actually operating through the messy environment of the body. A close look at what has been done and what remains to be done suggests that the metaphor of the “therapeutic missile” is neither sufficient, nor even necessary. Recent developments in nanomedicine suggest that therapeutic efficacy cannot be obtained without negotiating with the biological milieu and taking advantage of what it affords. An ‘oikological’ approach seems more appropriate, more heuristic and more promising than the popular missile. It is based on the view of organism as an oikos that has to be carefully managed. The dispositions of nanocapsules have to be coupled with the affordances of the environment. As it requires dealing with nanoparticles as relational entities (defined by their potential for interactions) rather than as stable substances (defined by intrinsic properties) this metaphor eventually might well change research priorities in nanotechnology in general. (shrink)

A major problem in the treatment of cancer is the specific targeting of anti‐tumor drugs to these abnormal cells. Ideally, such a drug should act over short distances to minimize damage to healthy cells, and target subcellular compartments that have the highest sensitivity to the drug. Photosensitizers, alpha‐emitting radionuclides and many other medicines could be considered as such drugs if they possessed cellular and subcellular specificity. The author describes a novel approach of using modular recombinant transporters to target (...) photosensitizers and alpha‐emitting radionuclides to the nucleus, where their action is most pronounced, of cancer cells. Photosensitizer‐transporter conjugates have up to 3000 times greater efficacy than free photosensitizers and display cell specificity in contrast to free photosensitizers. Alpha‐emitting radionuclides, conjugated with the modular transporters, acquired similar properties. The different modules of the transporters are interchangeable, meaning that they can be tailored for particular applications. BioEssays 30:278–287, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain‐of‐function mutations, in general, has been productive. However, (...) it has been a major challenge to use standard pharmacologic approaches to target loss‐of‐function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. (shrink)

Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK—requiring knowledge of which RTKs are upregulated in any given tumour—strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a (...) common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking—in particular, aberrant post‐translational modifications in cancers that contribute to dysregulated endosomal trafficking—could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth. (shrink)

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s (...) when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. (shrink)

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s (...) when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent. (shrink)

This paper builds on previous work that investigated anticancer drugs as ‘informed materials’, i.e., substances that undergo an informational enrichment that situates them in a dense relational web of qualifications and measurements generated by clinical experiments and clinical trials. The paper analyzes the recent transformation of anticancer drugs from ‘informed’ to ‘informing material’. Briefly put: in the post-genomic era, anti-cancer drugs have become instruments for the production of new biological, pathological, and therapeutic insights into the underlying etiology and evolution of (...) cancer. Genomic platforms characterize individual patients’ tumors based on their mutational landscapes. As part of this new approach, drugs targeting specific mutations transcend informational enrichment to become tools for informing their targets, while also problematizing the very notion of a ‘target’. In other words, they have become tools for the exploration of cancer pathways and mechanisms. While several studies in the philosophy and history of biomedicine have called attention to the heuristic relevance and experimental use of drugs, few have investigated concrete instances of this role of drugs in clinical research. (shrink)

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. (...) DNA in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

Optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are important research tools in recent neurobiology. These tools allow unprecedented control over activity in specifically targeted neurons in behaving animals. Two approaches in philosophy of neuroscience, mechanism and ruthless reductionism, provide explicit accounts of experiments and results using tools like these, but each offers a different picture about how levels of mechanisms relate. I argue here that the ruthless reductionist’s direct mind‐to‐cellular/molecular activities linkages “in a single bound” better fits (...) with both the experimental designs using these tools and some of the scientists’ own judgments about their results than does the mechanist’s “nested hierarchies of mechanisms‐within‐mechanisms.” So at least some important work in current neuroscience appears to be ruthlessly reductive. Mechanism may not correctly characterize all current work in neuroscience, despite its recent popularity. (shrink)

Efforts by governments, firms, and patients to deliver pioneering drugs for critical health needs face a challenge of diminishing efficiency in developing those medicines. While multi-sectoral collaborations involving firms, researchers, patients, and policymakers are widely recognized as crucial for countering this decline, existing incentives to engage in drug development predominantly target drug manufacturers and thereby do little to stimulate collaborative innovation. In this mini review, we consider the unexplored potential within pharmaceutical regulations to create novel incentives to encourage (...) a diverse set of actors from the public and private spheres to engage in the kind of collaborative knowledge exchange requisite for fostering enhanced innovation in early drug development. (shrink)

The COVID-19 pandemic has resulted in more than 524 million cases and 6 million deaths worldwide. Various drug interventions targeting multiple stages of COVID-19 pathogenesis can significantly reduce infection-related mortality. The current within-host mathematical modeling study addresses the optimal drug regimen and efficacy of combination therapies in the treatment of COVID-19. The drugs/interventions considered include Arbidol, Remdesivir, Interferon and Lopinavir/ritonavir. It is concluded that these drugs, when administered singly or in combination, reduce the number of infected cells and (...) viral load. Four scenarios dealing with the administration of a single drug, two drugs, three drugs and all four are discussed. In all these scenarios, the optimal drug regimen is proposed based on two methods. In the first method, these medical interventions are modeled as control interventions and a corresponding objective function and optimal control problem are formulated. In this framework, the optimal drug regimen is derived. Later, using the comparative effectiveness method, the optimal drug regimen is derived based on the basic reproduction number and viral load. The average number of infected cells and viral load decreased the most when all four drugs were used together. On the other hand, the average number of susceptible cells decreased the most when Arbidol was administered alone. The basic reproduction number and viral load decreased the most when all four interventions were used together, confirming the previously obtained finding of the optimal control problem. The results of this study can help physicians make decisions about the treatment of the life-threatening COVID-19 infection. (shrink)

There are a number of premises underlying much of the vigorous debate on pharmacological cognitive enhancement. Among these are claims in the enhancement literature that such drugs exist and are effective among the cognitively normal. These drugs are deemed to enhance cognition specifically, as opposed to other non-cognitive facets of our psychology, such as mood and motivation. The focus on these drugs as cognitive enhancers also suggests that they raise particular ethical questions, or perhaps more pressing ones, compared to those (...) raised by other kinds of neuroenhancement. Finally, the use of these drugs is often claimed to be significant and increasing. Taken together, these premises are at the heart of the flurry of debate on pharmacological cognitive enhancement. In this article, it is argued that these are presumptions for which the evidence does not hold up. Respectively, the evidence for the efficacy of these drugs is inconsistent; neurologically it makes little sense to distinguish the cognitive from non-cognitive as separate targets of pharmacological intervention; ethically, the questions raised by cognitive enhancement are in fact no different from those raised by other kinds of neuroenhancement; and finally the prevalence rates of these drugs are far from clear, with the bulk of the claims resting on poor or misrepresented data. Greater conceptual clarity along with a more tempered appreciation of the evidence can serve to deflate some of the hype in the associated literature, leading to a more realistic and sober assessment of these prospective technologies. (shrink)

The current strategy of searching for an effective treatment for COVID-19 relies mainly on repurposing existing therapies developed to target other diseases. Conflicting results have emerged in regard to the efficacy of several tested compounds but later results were negative. The number of conducted and ongoing trials and the urgent need for a treatment pose the risk that false-positive results will be incorrectly interpreted as evidence for treatments’ efficacy and a ground for drug approval. Our purpose is twofold. First, (...) we show that the number of drug-repurposing trials can explain the false-positive results. Second, we assess the evidence for treatments’ efficacy from the perspective of evidential pluralism and argue that considering mechanistic evidence is particularly needed in cases when the evidence from clinical trials is conflicting or of low quality. Our analysis is an application of the program of Evidence Based Medicine Plus to the drug repurposing trials for COVID. Our study shows that if decision-makers applied EBM+, authorizing the use of ineffective treatments would be less likely. We analyze the example of trials assessing the efficacy of hydroxychloroquine as a treatment for COVID-19 and mechanistic evidence in favor of and against its therapeutic power to draw a lesson for decision-makers and drug agencies on how excessive hypothesis testing can lead to spurious findings and how studying negative mechanistic evidence can be helpful in discriminating genuine from spurious results. (shrink)

Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies as (...) well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between development methodology and actual therapeutic success. (shrink)

A better understanding of how schistosomes exploit host nutrients, neuro‐endocrine hormones and signalling pathways for growth, development and maturation may provide new insights for improved interventions in the control of schistosomiasis. This paper describes recent advances in the identification and characterisation of schistosome tyrosine kinase and signalling pathways. It discusses the potential intervention value of insulin signalling, which may play an important role in glucose uptake and carbohydrate metabolism in schistosomes, providing the nutrients essential for parasite growth, development and, notably, (...) female fecundity. Significant progress has also been made in the characterisation of other schistosome growth factor receptors, such as transforming growth factor beta receptor and epidermal growth factor receptor, and in our understanding of their roles in the host‐parasite molecular dialogue and parasite development. The use of parasite signal transduction components as novel vaccine or drug targets may prove invaluable in prevention, treatment and control strategies to combat schistosomiasis. (shrink)

Chemotherapy is an important therapeutic approach for cancer treatment. However, drug resistance is an obstacle that often impairs the successful use of chemotherapies. Therefore, overcoming drug resistance would lead to better therapeutic outcomes for cancer patients. Recently, studies by our own and other groups have demonstrated that there is an intimate correlation between the loss of the F‐box and WD repeat domain‐containing 7 (FBW7) tumor suppressor and the incurring drug resistance. While loss of FBW7 sensitizes cancer cells (...) to certain drugs, FBW7‐/‐ cells are more resistant to other types of chemotherapies. FBW7 exerts its tumor suppressor function by promoting the degradation of various oncoproteins that regulate many cellular processes, including cell cycle progression, cellular metabolism, differentiation, and apoptosis. Since loss of the FBW7 tumor suppressor is linked to drug resistance, FBW7 may represent a novel therapeutic target to increase drug sensitivity of cancer cells to conventional chemotherapeutics. This paper thus focuses on the new functional aspects of FBW7 in drug resistance. (shrink)

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so‐called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general (...) analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non‐peptide scaffolds. (shrink)

Recreational Drugs European Network (ReDNet) project aims to use the Psychonaut Web Mapping Project database (Psychonaut Web Mapping Group, 2009) containing novel psychoactive compounds usually not mentioned in the scientific literature and thus unknown to clinicians as a unique source of information. The database will be used to develop an integrated ICT prevention approach targeted at vulnerable individuals and focused on novel synthetic and herbal compounds and combinations. Particular care will be taken in keeping the health professionals working directly with (...) young people showing problematic behaviors regularly updated in terms of novel compounds and combinations as well. A user-friendly project website will be developed aimed primarily at delivering the information/prevention approaches, but will also be a way of communicating with project partners and relevant stakeholders (e.g. thematic forum facilities, instant messages, blogs, video chat, wikiblog, newsletters distributed via mailing list). The website will support various ICT prevention tools, including an SMS alert service. Different areas and sections will be aimed specifically at the different target groups. -/- . (shrink)

In light of the central role that medications play in medical progress, the declining rate of new drug development over the past decade is cause for concern . Without important breakthroughs in drug discovery, the future will not be auspicious for the many people suffering from chronic and incurable illnesses. The sluggish pace of pharmaceutical innovation has been particularly characteristic of the largest drug manufacturers, which have generally focused their energies on potential blockbuster medications, those that can (...) generate over $1 billion in annual revenue . Given Pharma’s struggles, the success of the country’s largest drug manufacturer in bringing the .. (shrink)

Brian Earp and his colleagues argue in this issue’s target article that racial justice requires ending the War on Drugs. In this they are absolutely correct. Indeed, de...

Activating the ERK pathway (extracellular signal‐regulated kinase pathway) has proven beneficial in several models of Huntington's disease (HD), and drugs that are protective in HD models have recently been found to activate ERK. Thus, the ERK cascade may be a potential target for therapeutic intervention in this currently untreatable disorder. HD is caused by an expanded polyglutamine repeat in the huntingtin (Htt) protein that actuates a diverse set of pathogenic mechanisms. In response to mutant Htt, ERK is activated and directs (...) a protective transcriptional response and inhibits caspase activation. Paradoxically, Htt also interferes with several signaling events of the ERK pathway. Mutant Htt compromises the ERK‐dependent transcriptional response to corticostriatal BDNF signaling. Mutant Htt also hinders glutamate uptake from the synaptic cleft by down‐regulating ERK‐dependent expression of glutamate transporters, leaving cells vulnerable to excitotoxicity. Some of this cellular complexity can be capitalized on to achieve selective activation of ERK, which can be protective. (shrink)

With the human genome mapped, and with the mapping of more than one hundred animal genomes in progress, the amount of genetic data available is increasing exponentially. This exponential increase in data is having an immediate impact on the process of drug development. By using techniques of information technology to manipulate data regarding the genes, proteins, and biochemical pathways associated with various diseases, scientists are beginning to be able to design drugs in a systematic fashion. In the context of (...) any given disease, scientists look to see whether a gene, a protein for which the gene codes, or another protein in the relevant biochemical pathway could be the “target” biological molecule, the “knocking out” of which would halt or slow the disease's progression. Once a target molecule has been identified and characterized structurally, drug therapies that would be likely to knock out this target can be identified and tested systematically. The merger of information technology and genetic technology has changed the process of pharmaceutical development so much that a new term—bioinformatics—has been coined to describe this new approach to such development. (shrink)

Brand-name prescription drug manufacturers use various strategies to extend their market exclusivity periods by delaying generic or biosimilar competition. Recent Congressional legislation has targeted four such tactics. We analyze these proposals and assess their likely effect on competition in the U.S. drug market.

Current suggestions for capacities that should be targeted for moral enhancement has centered on traits like empathy, fairness or aggression. The literature, however, lacks a proper model for understanding the interplay and complexity of moral capacities, which limits the practicability of proposed interventions. In this paper, I integrate some existing knowledge on the nature of human moral behavior and present a formal model of prosocial motivation. The model provides two important results regarding the most friction-free route to moral enhancement. First, (...) we should consider decreasing self-interested motivation rather than increasing prosociality directly. Second, this should be complemented with cognitive enhancement. These suggestions are tested against existing and emerging evidence on cognitive capacity, mindfulness meditation and the effects of psychedelic drugs and are found to have sufficient grounding for further theoretical and empirical exploration. Furthermore, moral effects of the latter two are hypothesized to result from a diminished sense of self with subsequent reductions in self-interest. (shrink)

In the last few years, annexins have been discovered in several nematodes and other parasites, and distinct differences between the parasite annexins and those of the hosts make them potentially attractive targets for anti‐parasite therapeutics. Annexins are ubiquitous proteins found in almost all organisms across all kingdoms. Here, we present an overview of novel annexins from parasitic organisms, and summarize their phylogenetic and biochemical properties, with a view to using them as drug or vaccine targets. Building on (...) structural and biological information that has been accumulated for mammalian and plant annexins, we describe a predicted additional secondary structure element found in many parasite annexins that may confer unique functional properties, and present a specific antigenic epitope for use as a vaccine. (shrink)

In all domains of life, transmembrane proteins from the ATP‐binding cassette (ABC) transporter family drive the translocation of diverse substances across lipid bilayers. In pathogenic fungi, the ABC transporters of the pleiotropic drug resistance (PDR) subfamily confer antibiotic resistance and so are of interest as therapeutic targets. They also drive the quest for understanding how ABC transporters can generally accommodate such a wide range of substrates. The Pdr5 transporter from baker's yeast is representative of the PDR group and, (...) ever since its discovery more than 30 years ago, has been the subject of extensive functional analyses. A new perspective of these studies has been recently provided in the framework of the first electron cryo‐microscopy structures of Pdr5, as well as emergent applications of machine learning in the field. Taken together, the old and the new developments have been used to propose a mechanism for the transport process in PDR proteins. This mechanism involves a “flippase” step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux. (shrink)

ADP‐ribosylation is a post‐translational modification catalyzed by writer enzymes – ADP‐ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP‐ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP‐ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and (...) development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future. (shrink)

Recent advances in brain imaging methods as well as increased sophistication in neuroscientific modeling of the brain’s reward systems have facilitated the study of neural mechanisms associated with addiction such as processes associated with motivation, decision-making, pleasure seeking, and inhibitory control. These scientific activities have increased optimism that the neurological underpinnings of addiction will be delineated, and that pharmaceuticals that target and change these mechanisms will by themselves facilitate early intervention and even full recovery. In this paper, we argue that (...) it is misguided to construe addiction as just or primarily a brain chemistry problem, which can be adequately treated by pharmaceutical interventions alone. (shrink)

The target of my discussion is intuitions lay people have about justice in the context of drug policy—intuitions that take on a more or less moral-desert-based shape. I argue that even if we think desert is the right measure of how we ought to treat people, we ought still be in favour of Harm Reduction measures for people who use drugs. Harm Reduction measures are controversial with members of the public, and much of the opposition seems to come from (...) something like an appeal to a desert conception of justice—the notion that a just state of affairs is one in which everybody gets what they deserve, no more, no less. A recent study, for example, found that ‘moral outrage’ predicts a preference for prevalence reduction over Harm Reduction. The thinking seems to be that, since drug use is wrong, letting people who use drugs suffer and/or die as a consequence of their use is just. Aiding their health and safety, while perhaps compassionate, is unjust. I argue that there is a bad desert fit between using drugs and suffering avoidable harm even if using drugs is morally wrong. Many of the possible harms of drug use are socially/policy driven, and much problematic drug use is context dependent, not cleanly attributable to the decisions of the person who uses drugs. This means that even if drug use is wrong, people who use drugs deserve Harm Reduction policies, at minimum. (shrink)