Abstract:
:There is an increasing need to rapidly determine the specificity of proteases that potentially play a role in human and animal disease. Substrates for novel proteases can be discovered by testing standard protease substrates such as oxidized insulin B-chain, by screening commercially available substrates for other proteases, or by preparing derivatives of known biological targets. The relative importance of each substrate residue can be determined through alanine-scanning, or by preparing incremental changes at one or more positions within the known substrate. More efficient methods such as coupled liquid chromatography - mass spectrometry (LC-MS) or C-terminal/N-terminal sequencing of reaction products allow the selection of improved substrates from mixtures of peptides. In other cases mixtures of substrates can be spatially segregated prior to protease treatment during chemical synthesis on beads or membranes. Positional scanning libraries can be used to find substrates for proteases with interdependent subsites, while minimizing required synthetic and screening effort. As proteases catalyze both hydrolysis and amide bond formation, acyl transfer from protease-substrate intermediates to mixtures of peptide nucleophiles provide substrate sequence information. Genetic methods including substrate phage display, retroviral display, bacterial display, and yeast alpha-halo assays combine selection with the ability to propagate selected sequences and directly deconvolute the cleaved peptide via sequencing of substrate-coding DNA. This review describes various methods for optimizing protease substrates for biological activity and the use of optimized substrates in pharmaceutical discovery.
journal_name
Curr Pharm Desjournal_title
Current pharmaceutical designauthors
Richardson PLdoi
10.2174/1381612023392630subject
Has Abstractpub_date
2002-01-01 00:00:00pages
2559-81issue
28eissn
1381-6128issn
1873-4286journal_volume
8pub_type
杂志文章,评审abstract::Monocytes are leading component of the mononuclear phagocytic system that play a key role in phagocytosis and removal of several kinds of microbes from the body. Monocytes are bone marrow precursor cells that stay in the blood for a few days and migrate towards tissues where they differentiate into macrophages. Monocy...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612825666190102104642
更新日期:2018-01-01 00:00:00
abstract::Monoclonal antibodies have undergone a radical evolutionary journey over the last 25 years, with advances in molecular biology, process development and drug formulation underpinning their rise to becoming one of the most efficacious and economically important class of drug today. The success of antibodies for the trea...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612821666150310142202
更新日期:2015-01-01 00:00:00
abstract::The use of systematic approach for the analysis of mechanism of action of drugs at different levels of biological organization of organisms is an important task in experimental and clinical pharmacology for drug designing and increasing the efficacy and safety of drugs. The analysis of published data on pharmacologica...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612823666170829135115
更新日期:2018-01-01 00:00:00
abstract:OBJECTIVES:This paper reviews literary evidence on antithrombotic therapies currently employed in TAVR to assess validity and efficacy; duration and modality are also considered. In the absence of firm guidelines and reliable trial results, we analyze current knowledge of interaction between PPI and antithrombotic drug...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612811319220002
更新日期:2013-01-01 00:00:00
abstract::A positive relationship between stress tolerance and longevity has been observed in several model systems. That the same correlation is applicable in humans and that it may be open to experimental manipulation for extending human lifespan requires studies on association of stress genes with longevity. The involvement ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/138161210790883499
更新日期:2010-01-01 00:00:00
abstract::Since their proposal in 1976, sigma (σ) receptors have been increasingly implicated in the pathophysiology of virtually all major central nervous system (CNS) disorders, including anxiety, depression, schizophrenia, and drug addiction. Due to their involvement in motor function and higher cognitive function,σ recepto...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161212799436539
更新日期:2012-01-01 00:00:00
abstract::The use of the carbohydrate glucose as an energetic source is essential for an adequate function of the human body. The complex regulation of this molecule involves the coordinated action of various organs such as pancreas, liver and brain. Any disruption of this physiological balance may result in a dangerous comprom...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612822666151209152013
更新日期:2016-01-01 00:00:00
abstract:BACKGROUND:Antiepileptic treatment strategy plays an important role in the management of intracranial vascular malformations. The intracranial vascular malformations can be divided into cavernous hemangiomas, arteriovenous malformations, developmental venous anomalies and capillary telangiectasias. Seizures and hemorrh...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612823666171027142718
更新日期:2017-01-01 00:00:00
abstract::In the stomach, pre-absorptive perception of food constituents is of particular importance in maintaining secretion and motility that matches the quantity and quality of nutrients. Products of food protein hydrolysis, free amino acids and short peptides, are the most potent chemical stimulants of the gastric phase of ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/13816128113199990581
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:R. Schofield (1978) proposed a hypothesis of hematopoietic stem cells (HSCs) niche (specialized cell microenvironment). An existence of osteoblastic and vascular niches for HSCs has been postulated since 2003. At the same time, the discussion about the existence and functioning of niche for multipotent mesen...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612824666180829154119
更新日期:2018-01-01 00:00:00
abstract:BACKGROUND:The objective of this study was to apply Quality by Design (QbD) principles on process parameter optimization for the development of hybrid delivery system (combination of (SLNs) and In-situ gelling system) for hydrophilic drug Moxifloxacin Hydrochloride (MOX) to achieve its controlled delivery, which otherw...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/1381612824666180403115106
更新日期:2018-01-01 00:00:00
abstract::Pulmonary arterial hypertension (PAH) is a severe vascular complication of connective tissue diseases. In the context of systemic sclerosis (SSc), PAH is a devastating disease with a dramatic impact on prognosis and survival. Despite advances in early diagnosis and the development of new targeted treatments, SSc-relat...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161212799504704
更新日期:2012-01-01 00:00:00
abstract::RNA interference (RNAi) has quickly proven to be an immensely useful tool for studying gene function and validation of potential drug targets in almost all organisms that possess the required set of proteins of the interference pathway. In protozoan parasites like Plasmodium, Toxoplasma, Entamoeba, Giardia, Trypanosom...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/13816128113199990027
更新日期:2014-01-01 00:00:00
abstract::Inhibition of the renin-angiotensin system (RAS) has been shown to have beneficial effects in cardiovascular disease prognosis and therapy.Discovery of (pro)renin receptor [(P)RR] revealed that (P)RR upon binding to both renin or prorenin in their proenzyme inactive form made them enzymatically active, thus aiding the...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/13816128113199990472
更新日期:2014-01-01 00:00:00
abstract::An integrative synthesis of concepts and an explosion of experimental and epidemiological findings allow new insights as to how the interactions of genetic, environmental, dietary, cultural (social, psychological, economic) factors can influence the aging and diseases of aging processes. Although the net effect of the...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161208786264106
更新日期:2008-01-01 00:00:00
abstract::The heart is a sophisticated endocrine gland synthesizing a family of peptide hormones by three different genes. These cardiac hormones are stored as 3 prohormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) prohormones. Within the ANP prohormones are 4 ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161210790963887
更新日期:2010-01-01 00:00:00
abstract::Increased visceral adiposity, is an emerging cardiovascular risk factor. There is now a compelling need to quantify visceral adipose tissue not only for diagnostic purposes, but also for therapeutic interventions with weight reduction drugs or pharmaceuticals targeted to adipose tissue, as well as anti-obesity medicat...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161207781039670
更新日期:2007-01-01 00:00:00
abstract::Parkinson's disease (PD) is one of common neurodegenerative diseases, which shows motor symptoms including tremor, bradykinesia, rigidity and postural instability. It also involves non-motor symptoms such as cognitive impairment, mental manifestation, autonomic disorder and sensory disturbance. Although treatments to ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612823666170710163731
更新日期:2017-01-01 00:00:00
abstract::Apoptosis is a regulated process leading to cell death, which is implicated both in normal development and in various pathologies including heart failure, stroke and neurodegenerative diseases. Caspase-3, a key enzyme of the apoptotic pathway, is considered as a major target for the treatment of abnormal cell death. M...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161211795049679
更新日期:2011-01-01 00:00:00
abstract::The prevalence of type 2 diabetes is rising at an alarming rate worldwide. Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the diabetic population. Future CAD risk should be routinely assessed in patients with diabetes as specific subgroups might benefit from information derived from c...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161208786071272
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND:Arterial hypertension (AH) and peripheral arterial disease (PAD) frequently coincide. While significant attention is paid to AH, PAD is often underestimated. It is known that both AH and PAD present high cardiovascular risks for ischemic events. To date, the use of the most common anti-hypertensive drugs in ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612823666170608083605
更新日期:2017-01-01 00:00:00
abstract::In patients with acute coronary syndromes (ACS), hypertension is common. The type of ACS and severity of hypertension would determine the treatment algorithm. In ST elevation myocardial infarction (MI), time to reperfusion is essential whereas in malignant hypertension the reduction of blood pressure to prevent end or...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161207781663046
更新日期:2007-01-01 00:00:00
abstract::Cancer and tumor have been major reasons for numerous deaths in this century across the world. Many strategies have been designed to treat, diagnose, or prevent cancer. The success of chemotherapy largely depends on drug targeting. The advent of nanotechnology has vastly improved drug delivery for targeting and diagno...
journal_title:Current pharmaceutical design
pub_type: 杂志文章
doi:10.2174/1381612826666200720235752
更新日期:2020-01-01 00:00:00
abstract::There is extensive evidence that changes in immune system activation accompany the pathological changes of Alzheimer's disease (AD), but a mechanistic understanding of how the immune system actually participates in disease pathogenesis is still largely lacking. Because of the complexity of the immunological response, ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161205774370843
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:The 3' repair exonuclease 1 (TREX1) gene is the major DNA-specific 3'-5 'exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that pr...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612825666190902113218
更新日期:2019-01-01 00:00:00
abstract::Several lines of evidence support a mutual relationship between the nervous system and the immune system. Therefore, it is not surprising that some neuropsychiatric disorders are also characterized by immune abnormalities. In patients with phobic disorders and in patients with migraine without aura some common immune ...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612033454234
更新日期:2003-01-01 00:00:00
abstract::Protein stability of hypoxia-inducible factor (HIF)alpha subunits is regulated by the oxygen-sensing prolyl-4-hydroxylase domain (PHD) enzymes. Under oxygen-limited conditions, HIFalpha subunits are stabilized and form active HIF transcription factors that induce a large number of genes involved in adaptation to hypox...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161209789649411
更新日期:2009-01-01 00:00:00
abstract::Extracellular matrix (ECM) is composed of large collagen fibrils. Glycoproteins, such as fibronectin, can bind to collagen or form their own networks. Collagen fibrils are also decorated by proteoglycans, proteins that have large glycosaminoglycan sidechains. In addition, extracellular space often contains hyaluronan,...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161209787846720
更新日期:2009-01-01 00:00:00
abstract::Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes. Although the role of chemokine receptors (CKRs) in cancer biology is a relatively new field of study, a growing body of data suggest that a number of CKRs, including CXCR4, CCR4, CCR7, and CCR10, may play diverse...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/138161209787582165
更新日期:2009-01-01 00:00:00
abstract:BACKGROUND:The use of aromatic plants to relief different illness is not a new therapy. Actually aromatic plants have been used for many centuries by different cultures around the world. Pharmacological studies provide scientific support to the traditional use of aromatic medicinal plants and aromatherapy; nevertheless...
journal_title:Current pharmaceutical design
pub_type: 杂志文章,评审
doi:10.2174/1381612822666160607065917
更新日期:2016-01-01 00:00:00