Current opinion in drug discovery & development最新文献

Systems biology uses experimental and computational approaches to characterize large sample populations systematically, process large datasets, examine and analyze regulatory networks, and model reactions to determine how components are joined to form functional systems. Systems biology technologies, data and knowledge are particularly useful in understanding disease processes and drug actions. An important area of integration between systems biology and drug discovery is the concept of polypharmacology: the treatment of diseases by modulating more than one target. Polypharmacology for complex diseases is likely to involve multiple drugs acting on distinct targets that are part of a network regulating physiological responses. This review discusses the current state of the systems-level understanding of diseases and both the therapeutic and adverse mechanisms of drug actions. Drug-target networks can be used to identify multiple targets and to determine suitable combinations of drug targets or drugs. Thus, the discovery of new drug therapies for complex diseases may be greatly aided by systems biology.

The field of diagnostics has unprecedented opportunities to contribute to the practice of medicine in the era of targeted therapy and personalized healthcare. Rather than simply providing information regarding the presence and classification of disease, innovative molecular diagnostic tests will directly inform patient-management decisions, such as which targeted therapies to prescribe or whether a patient should be treated more aggressively. However, in order for diagnostics to deliver this high level of medical value, several challenges ranging from technical, pre-analytical, developmental, regulatory, reimbursement and quality perspectives need to be overcome. This review focuses on recent developments in each of these areas that are expected to improve the power and impact of diagnostics.

The last decades of the twentieth century ushered in the first treatments proven to modify the disease course of multiple sclerosis (MS). These breakthroughs in MS therapy stimulated an increase in the search for drugs with improved efficacy and greater ease of administration. This review summarizes the latest developments in the search for improved disease-modifying therapies and defines the efficacies and potential risks of such compounds. As with all new drugs, accurate assessments of risk:benefit ratios will be essential for the successful use of any agent targeting MS.

As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures.

Coronary artery disease consists of obstruction (stenosis) of the coronary arteries by the deposition of atherosclerotic plaques, resulting in an insufficient supply of oxygen to the heart muscle. Treatment options include the insertion of a stent - a metal mesh tube - into the obstructed vessel to keep the artery open, thus preventing acute occlusion and restenosis. The occlusion of vessels resulting from subacute stent thrombosis and late in-stent restenosis are potential complications after successful revascularization. However, the rate of stent thrombosis has been reduced dramatically by means of adequate antiplatelet therapy, and in-stent restenosis has been addressed successfully with drug-eluting stents. These drug-eluting stents are engineered to release bioactive agents into the affected blood vessels, plaques or tissues adjacent to the stent. Various antimitotic, anti-inflammatory, and anticoagulant immunosuppressive agents have been attached to stents, including sirolimus and tacrolimus. Future opportunities include the use of gene therapies released from gene-eluting stents. These advances highlight some of the opportunities for optimizing stent-based treatment for coronary artery disease.

The possibility of using the immune system of patients to control tumor outgrowth in a therapeutic setting has always been highly appealing to both clinicians and researchers. However, although cancer cells express tumor-associated antigens that can be targeted by T-cells, clinical trials suggest that the induction of specific immune responses per se may be insufficient to achieve clinical goals. Based on these trial data, in addition to experimental data revealing the complexity of mechanisms controlling immune responsiveness, a reassessment of immunotherapy procedures is underway. As a result, a second generation of antitumor treatments that includes reagents of potential pharmaceutical relevance is being developed. In this review, the most recent literature addressing issues related to immunotherapy for solid tumors is discussed.

The development of small molecular mass Hsp90 inhibitors has become an increasingly competitive field of research in recent years. Progress in preclinical and clinical research has provided increasing evidence that Hsp90 represents a promising molecular target for the treatment of cancer and other diseases. Although many challenges remain, recent clinical trial results for the most clinically advanced inhibitors indicate that clinical proof of concept in oncology therapy is achievable, and that Hsp90 inhibitors have the potential to contribute to the collection of anticancer treatments available to clinicians and patients in the near future.

Gene therapy holds considerable promise for the treatment of cardiovascular disease and may provide novel therapeutic solutions for both genetic disorders and acquired pathophysiologies such as arteriosclerosis, heart failure and arrhythmias. Recombinant DNA technology and the sequencing of the human genome have made a plethora of candidate therapeutic genes available for cardiovascular diseases. However, progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy. This review summarizes progress made toward the site-specific delivery of cardiovascular gene therapy and highlights selected promising novel approaches.

Sirolimus and tacrolimus are potent immunosuppressants that are delivered by drug-eluting stents (DES) for the prevention of in-stent restenosis. Balloon angioplasty with stent implantation has emerged as a successful treatment for coronary stenoses; angioplasty dilates the vessel lumen and the stent prevents elastic recoil of the vessel walls. However, angioplasty and stent placement both produce vascular injuries that potently stimulate the proliferation of smooth muscle cells, resulting in a thickening of the vascular wall. The purpose of DES is to deliver pharmacological agents that counteract neointimal hyperplasia. The sirolimus-eluting-stent reduces the incidence of in-stent restenosis significantly, whereas the tacrolimus-eluting-stent demonstrates no improvement in clinical benefit compared with a bare stent. Although sirolimus and tacrolimus have similar molecular structures, these drugs regulate immune activation via different mechanisms of action. The effects of this class of drugs are mediated by binding to the FK-506-binding proteins (FKBPs), which are highly evolutionarily conserved across species. This review highlights the structure and function of sirolimus, tacrolimus and FKBPs, with particular focus on recent observations that the two drugs target signaling pathways involved in the control of vascular smooth muscle apoptosis and proliferation directly.

HSV-1 is a neurotropic virus that displays several important adaptations to the nervous system of the host organism, each of which can be rationally exploited in the design of gene therapy vectors for neurological applications. Replication-incompetent (replication-defective) helper-independent recombinant vectors are nontoxic tools for gene transfer that preserve most of the neurotropic features of HSV-1, particularly the ability to express genes after establishing latent infections, and are thus proficient candidates for therapeutic gene transfer in neurons. A clinical trial with the use of a replication-incompetent vector, NP-2 (Diamyd Inc), for the treatment of pain has been initiated. Attenuated replication-competent (oncolytic) vectors are becoming suitable and powerful tools to eradicate brain tumors, such as malignant gliomas, as a result of the ability to replicate and spread only within the tumor mass. Some attenuated replication-competent vectors, such as G-207 and HSV-1716 (Crusade Laboratories Ltd), have been used in clinical trials for the treatment of cancers including recurrent malignant glioma. Helper-dependent amplicon vector technology takes advantage of the capacity of the virus particle to accommodate < or = 150 Kbp of foreign DNA, enabling these vectors to deliver complete genomic loci to the nucleus of mammalian cells, making amplicons particularly useful agents in protocols that require stable and physiological transgene expression. However, difficulties in obtaining large stocks of helper-free amplicons continue to limit the use of these vectors in the clinic.