Trends in exploration of therapeutic targets

Lead discovery against a preselected therapeutic target is a key component in modern drug development. Continuous effort and increasing interest has been directed at the search for new targets, which has led to the identification of a growing number of them. Data from the therapeutic target database, at http://bidd.nus.edu.sg/group/cjttd/ttd.asp, show that, as of July 2004, the number of documented targets of marketed and investigational drugs has reached 1,174 distinct proteins (including subtypes) and 27 nucleic acids, 239 of which are targets of the marketed drugs. Analysis of these targets, particularly those of recently approved drugs and patented investigational agents, provide useful hints about general trends of target exploration and current focus in drug discovery for the treatment of high impact diseases needing effective or more treatment options.     

心衰治疗靶点与干预研究进展

随着对心衰发病、进程以及恶化病理生理过程了解的不断深入,心衰新靶点的干预正在成为治疗心衰的希望。文中综述了心肌肥厚过程中包括钙调神经磷酸酶(CaN)、G蛋白、糖原合酶激酶3(GSK3)、肌细胞增强因子2(MEF2)、过氧化物酶体增生激活受体(PPAR)、小G蛋白(smallG protein)、Na+/H+交换体(NHE)、亚细胞器(subcellular organelles)的治疗靶点,以及天冬氨酸特异性半胱氨酸蛋白酶(Caspase)、核酸内切酶、凋亡调节因子等细胞凋亡治疗靶点与干预,同时,也综述了内皮素及受体、炎性因子及贫血治疗新靶点的干预药物、干预措施及机制,为心衰治疗、新药研发提供思路。     

Trends in the exploration of therapeutic targets for the treatment of endocrine, metabolic and immune disorders

A number of therapeutic targets have been explored for developing drugs in the treatment of endocrine, metabolic and immune disorders. Continuous efforts and increasing interest have been directed at the search of new targets. Data from the therapeutic target database at http://bidd.nus.edu.sg/group/cjttd/ttd.asp, shows that there are 26, 24, and 22 targets of marketed drugs for the treatment of these three classes of diseases, respectively. The number of targets of investigational agents has reached 98, 124, and 72, respectively. An analysis of these targets, particularly those of recently approved drugs and patented investigational agents, provides useful hint about the general trends of target exploration, with current focus on drug discovery and the difficulties encountered in developing drugs against these targets. Multiple profiles of these targets have been analyzed to probe the sequence, structural, physicochemical and systems-related features contributing to the successful exploration of a target against these diseases.     

银屑病治疗靶点及其药物研发进展

银屑病的发病机制未能完全阐明,近年来大量的实验和临床研究证实,银屑病可能是T细胞介导的自身免疫性疾病。这一发病过程涉及了很多靶点的激活,T细胞增殖和细胞因子的作用。目前,基于这些靶点研发治疗银屑病的新药已取得了长足的进展,本文就近年来银屑病靶向药物研究进展作一综述,为开发新的靶向药物提供参考。     

Ischemic stroke and glucose intolerance: a review of the evidence and exploration of novel therapeutic targets

Stroke is one of the leading causes of death and disability worldwide. It is well known that hyperglycemia and/or diabetes potentially exacerbate the neuronal damage observed following ischemic stroke. Recent reports have shown that hyperglycemia/glucose intolerance may be induced by cerebral ischemic stress, and that normalization of blood glucose levels during the first 48 h of hospitalization appears to confer greater survival outcomes in stroke patients. However, the mechanisms underlying post-ischemic glucose intolerance remain unclear. Here, we review research to date on the mechanisms through which ischemic neuronal damage develops and on the role of post-ischemic glucose intolerance focusing on insulin and adiponectin signaling and communication between the brain and peripheral tissues. The relationship between ischemic neuronal damage and post-ischemic glucose intolerance is also discussed. With respect to therapeutic options, in addition to traditional post-stroke therapies, we also discuss the effect of anti-diabetic drugs and glucose-sensing neuropeptides on the development of the post-ischemic glucose intolerance and neuronal damage. In conclusion, we support the idea for focusing research on the development of post-ischemic glucose intolerance as a new therapeutic target for the stroke patients.     

国外药物靶标开发的现状及特点分析

药物通过结合并调节特定的蛋白或核酸靶标的活性而发挥其治疗作用.大量的药物靶标已经被开发并用于创新药物的发现过程.目前的研究重点是寻找新的靶标和对现有靶标进行更为深入地研究.分析药物靶标开发的现状和特点将有助于我们理解药物的分子作用机制,发现药物靶标开发中涉及的一些规律性的东西,为我国的创新药物开发提供参考.     

Emerging therapeutic targets in psoriasis

Biopharmaceuticals that target specific disease-mediating molecules have advanced our understanding of the pathogenesis of psoriasis. The traditional paradigm that psoriasis is primarily a disease of epidermal cells has been replaced with a model that now includes keratinocyte-derived factors, inflammatory mediators and angiogenic mechanisms. Recent studies have highlighted some of the key molecules involved in all of these pathogenic processes. Several have already been evaluated as putative targets in in vitro and in vivo studies, whereas other molecules are significantly upregulated in psoriasis and require further study to elucidate their role and contribution to disease. Although not all these molecules will eventually qualify as drug targets, data from similar experimental strategies are predicted to underpin the next generation of candidate targets and novel therapeutic approaches.     

Antioxidant therapeutic targets in COPD

Oxidative stress and chronic inflammation are important features in the pathogenesis of chronic obstructive pulmonary disease (COPD). Oxidative stress has important consequences for several elements of lung physiology and for the pathogenesis of COPD, including oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. Therefore, targeting oxidative stress with antioxidants or boosting the endogenous levels of antioxidants is likely to be beneficial in the treatment of COPD. Antioxidant and/or anti-inflammatory agents such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn), dietary polyphenol (curcumin-diferuloylmethane, a principal component of turmeric), resveratrol (a flavanoid found in red wine), green tea (theophylline and epigallocatechin-3- gallate), ergothioneine (xanthine and peroxynitrite inhibitor), quercetin, erdosteine and carbocysteine lysine salt, have been reported to control NF-kappaB activation, regulation of glutathione biosynthesis genes, chromatin remodeling and hence inflammatory gene expression. Specific spin traps such as alpha-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), manganese (III) meso-tetrakis (N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150 and AEOL 10113), and a SOD mimetic M40419 have also been reported to inhibit cigarette smoke-induced inflammatory responses in vivo. Since a variety of oxidants, free radicals and aldehydes are implicated in the pathogenesis of COPD it is possible that therapeutic administration of multiple antioxidants will be effective in the treatment of COPD. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in COPD are discussed.     

Epigenetics and therapeutic targets in gastrointestinal malignancies

Gastrointestinal (GI) malignancies account for substantial mortality and morbidity worldwide. They are generally promoted by dysregulated signal transduction and epigenetic pathways, which are controlled by specific enzymes. Recent studies demonstrated that histone deacetylases (HDACs) together with DNA methyltransferases (DNMTs) have crucial roles in the signal transduction/epigenetic pathways in GI regulation. In this review, we discuss various enzyme targets and their functional mechanisms responsible for the regulatory processes of GI malignancies. We also discuss the epigenetic therapeutic targets that are mainly facilitated by DNMT and HDAC inhibitors, which have functional consequences and clinical outcomes for GI malignancies.     

Integrins as therapeutic targets

Integrins are a large family of molecules that are central regulators in multicellular biology. They orchestrate cell-cell and cell-extracellular matrix (ECM) adhesive interactions from embryonic development to mature tissue function. Diverse human pathologies involve integrin adhesion, including thrombotic diseases, inflammation, cancer, fibrosis and infectious diseases. Integrins are exciting pharmacological targets because they are exposed on the cell surface and are sensitive to pharmacological blockade, but the scale of current efforts involving integrin therapeutics continues to surprise. Several therapeutics targeting integrins are effective drugs: five have been approved for use in clinic, with combined sales of over $1.5 billion in 2010 (based on company reports from that year). We gathered information from three major drug-trial databases and found that ～260 anti-integrin drugs have entered clinical trials. Here we overview integrins as drug targets and focus on cancer.     

Integrins as therapeutic targets

Integrins are widely expressed receptors that primarily function as mediators of cell-extracellular matrix interactions. They have multiple physiological roles, and alterations in their structure and function result in pathological conditions in multicellular organisms. Selective targeting of integrins is a therapeutic modality that can impact disease processes which are major causes of morbidity and mortality. This is most clearly seen in vascular disease, where anti-integrin agents are routinely used for treating acute ischaemic myocardial conditions. In the future, therapeutic targeting of integrins may also play a role in the treatment of inflammatory and neoplastic conditions. In this review we discuss the mechanisms whereby integrins are involved in thrombotic vascular conditions, inflammation and neoplasia, and outline how they can be targeted as therapeutic modalities.     

Emerging therapeutic targets in the short QT syndrome

Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable.

Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome.

Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K⁺ channel inhibitors. A combination of K⁺ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K⁺ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.     

Potential therapeutic targets in cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy is a recently identified pathological condition defined as "a chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease". Overall there seems to be a link between the progression of liver function impairment, the development of portal hypertension and the degree of hyperdynamic circulation, the hallmark of the deranged cardiovascular function in advanced liver diseases. Although mechanical factors contribute to much of the increased resistance within the liver in portal hypertension, there is clearly a vasculogenic component to the development, perpetuation and progression of this syndrome as well. The vascular component of portal hypertension includes an increase in splanchnic blood flow, as well as an increase in intrahepatic vascular resistance. Dysregulation of the nitric oxide system appears to play a key role in both these processes with a paradoxical reduction of intrahepatic availability despite increased disposal in the splanchnic and other vascular districts with adverse effects on cardiac function and structure. Nevertheless, other putative mediators of cardiac damage in cirrhosis have been proposed and their role in the pathogenesis of cirrhotic cardiomyopathy investigated. This review involves a discussion of data achieved on pathogenesis and clinical features of cirrhotic cardiomyopathy but mainly focuses on considerations on potential therapeutic targets, in the light of the evidence that this mainly subclinical condition merges to clinical relevance when challenged with those therapeutic interventions and procedures currently employed to treat the major complications of cirrhosis that might produce a negative impact on the cardiovascular system.