Drug Target Insights[JOURNAL]
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136 papers
Drug Target Exploitable Structural Features of Adenylyl Cyclase Activity in Schistosoma mansoni.
Mbah AN, Kamga HL, Awofolu OR … +1 more , Isokpehi RD
Drug Target Insights · 2012 · PMID 23133313 · Full text
The draft genome sequence of the parasitic flatworm Schistosoma mansoni (S. mansoni), a cause of schistosomiasis, encodes a predicted guanosine triphosphate (GTP) binding protein tagged Smp_059340.1. Smp_059340.1 is pred...
The draft genome sequence of the parasitic flatworm Schistosoma mansoni (S. mansoni), a cause of schistosomiasis, encodes a predicted guanosine triphosphate (GTP) binding protein tagged Smp_059340.1. Smp_059340.1 is predicted to be a member of the G protein alpha-s subunit responsible for regulating adenylyl cyclase activity in S. mansoni and a possible drug target against the parasite. Our structural bioinformatics analyses identified key amino acid residues (Ser53, Thr188, Asp207 and Gly210) in the two molecular switches responsible for cycling the protein between active (GTP bound) and inactive (GDP bound) states. Residue Thr188 is located on Switch I region while Gly210 is located on Switch II region with Switch II longer than Switch I. The Asp207 is located on the G3 box motif and Ser53 is the binding residue for magnesium ion. These findings offer new insights into the dynamic and functional determinants of the Smp_059340.1 protein in regulating the S. mansoni life cycle. The binding interfaces and their residues could be used as starting points for selective modulations of interactions within the pathway using small molecules, peptides or mutagenesis.
17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells.
Sarangi U, Paithankar KR, Kumar JU … +2 more , Subramaniam V, Sreedhar AS
Drug Target Insights · 2012 · PMID 22915839 · Full text
Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therape...
Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA-β-gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21(CIP/WAF-1) and was accelerated in the absence of functional Hsp90. Sustained p16(INK4a) and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROS)i] and [(Ca(2+))i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt) and proliferative (ERK1/2) kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments.
Expression of Luteinizing Hormone Receptor in the Gastrointestinal Tract in Patients with and without Dysmotility.
Hammar O, Veress B, Montgomery A … +1 more , Ohlsson B
Drug Target Insights · 2012 · PMID 22563234 · Full text
Leuprolide is a gonadotropin-releasing hormone (GnRH) analog which has been shown to reduce symptoms in patients with irritable bowel syndrome (IBS) and chronic intestinal pseudo-obstruction (CIPO). The mechanism is not...
Leuprolide is a gonadotropin-releasing hormone (GnRH) analog which has been shown to reduce symptoms in patients with irritable bowel syndrome (IBS) and chronic intestinal pseudo-obstruction (CIPO). The mechanism is not known, but one hypothesis is through down-modulation of luteinizing hormone (LH) secretion, a hormone whith antagonistic effect on gastrointestinal motility. However, presence of LH receptors in the gastrointestinal tract has never been described. The aim of this study was to find one possible way of action for leuprolide by examining the presence of the LH receptor, and if present, to see whether there was different expression in patients with or without dysmotility. Full-thickness biopsies from the bowel wall of patients with and without severe dysmotility were examined using immunohistochemistry staining. Biopsies showed expression of LH receptors on myenteric neurons and in glial cells, neutrophils, endothelial cells and mast cells. There was no difference in expression between patient groups.
Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent.
Annabi B, Lord-Dufour S, Vézina A … +1 more , Béliveau R
Drug Target Insights · 2012 · PMID 22523472 · Full text
The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects,...
The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet-derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I-IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I-III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-κB. We found that resveratrol efficiently reversed the PMA-induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IκB phosphorylation in siSirt1-transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-κB signal transduction inhibitor independent of Sirt1.
Predictors of Virologic Failure in HIV/AIDS Patients Treated with Highly Active Antiretroviral Therapy in Brasília, Brazil During 2002-2008.
Bello EJ, Correia AF, Marins JR … +2 more , Merchan-Hamann E, Kanzaki LI
Drug Target Insights · 2011 · PMID 22174569 · Full text
Little data exists concerning the efficacy of the antiretroviral therapy in the Federal District in Brazil, therefore in order to improve HIV/AIDS patients' therapy and to pinpoint hot spots in the treatment, this resear...
Little data exists concerning the efficacy of the antiretroviral therapy in the Federal District in Brazil, therefore in order to improve HIV/AIDS patients' therapy and to pinpoint hot spots in the treatment, this research work was conducted. Of 139 HIV/AIDS patients submitted to the highly active antiretroviral therapy, 12.2% failed virologically. The significant associated factors related to unresponsiveness to the lentiviral treatment were: patients' place of origin (OR = 3.28; IC95% = 1.0-9.73; P = 0.032) and Mycobacterium tuberculosis infection (RR = 2.90; IC95% = 1.19-7.02; P = 0.019). In the logistic regression analysis, the remaining variables in the model were: patients' birthplace (OR = 3.28; IC95% = 1.10-9.73; P = 0.032) and tuberculosis comorbidity (OR = 3.82; IC95% = 1.19-12.22; P = 0.024). The patients enrolled in this survey had an 88.0% therapeutic success rate for the maximum period of one year of treatment, predicting that T CD4(+) low values and elevated viral loads at pretreatment should be particularly considered in tuberculosis coinfection, besides the availability of new antiretroviral drugs displaying optimal activity both in viral suppression and immunological reconstitution.
Repercussion of Mitochondria Deformity Induced by Anti-Hsp90 Drug 17AAG in Human Tumor Cells.
Vishal C, Kumar JU, Veera Brahmendra Swamy C … +5 more , Nandini R, Srinivas G, Kumaresan R, Shashi S, Sreedhar AS
Drug Target Insights · 2011 · PMID 22087060 · Full text
Inhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of...
Inhibiting Hsp90 chaperone roles using 17AAG induces cytostasis or apoptosis in tumor cells through destabilization of several mutated cancer promoting proteins. Although mitochondria are central in deciding the fate of cells, 17AAG induced effects on tumor cell mitochondria were largely unknown. Here, we show that Hsp90 inhibition with 17AAG first affects mitochondrial integrity in different human tumor cells, neuroblastoma, cervical cancer and glial cells. Using human neuroblastoma tumor cells, we found the early effects associated with a change in mitochondrial membrane potential, elongation and engorgement of mitochondria because of an increased matrix vacuolization. These effects are specific to Hsp90 inhibition as other chemotherapeutic drugs did not induce similar mitochondrial deformity. Further, the effects are independent of oxidative damage and cytoarchitecture destabilization since cytoskeletal disruptors and mitochondrial metabolic inhibitors also do not induce similar deformity induced by 17AAG. The 1D PAGE LC MS/MS mitochondrial proteome analysis of 17AAG treated human neuroblastoma cells showed a loss of 61% proteins from membrane, metabolic, chaperone and ribonucleoprotein families. About 31 unmapped protein IDs were identified from proteolytic processing map using Swiss-Prot accession number, and converted to the matching gene name searching the ExPASy proteomics server. Our studies display that Hsp90 inhibition effects at first embark on mitochondria of tumor cells and compromise mitochondrial integrity.
The effect of valproic Acid on mesenchymal pluripotent cell proliferation and differentiation in extracellular matrices.
Hatakeyama Y, Hatakeyama J, Takahashi A … +4 more , Oka K, Tsuruga E, Inai T, Sawa Y
Drug Target Insights · 2011 · PMID 21904447 · Full text
Valproic acid (2-n-propylpentanoic acid, VPA) is a widely used antiepileptic and anticonvulsant drug. Previous studies have reported that VPA effects osteogenesis in vivo and in vitro, yet it remains unclear whether VPA...
Valproic acid (2-n-propylpentanoic acid, VPA) is a widely used antiepileptic and anticonvulsant drug. Previous studies have reported that VPA effects osteogenesis in vivo and in vitro, yet it remains unclear whether VPA promotes cell differentiation of osteoblasts derived from mesenchymal cells. The purpose of this study was to clarify the effect of VPA on undifferentiated pluripotent mesenchymal cell proliferation and differentiation into osteoblasts while analyzing the impact of the absence or presence of extracellular matrices (ECMs). Mouse mesenchymal cells were cultured on non-coated plastic, type I collagen-coated, and fibronectin-coated plates in the absence or presence of VPA. A cell proliferation assay was performed in which modified formazan dye content was analyzed and proliferation nuclear antigen (PCNA)-positive cells were counted at various concentrations of VPA. A high concentration of VPA did not clearly alter cell morphology, but large numbers of stress fibers were observed in these cells and the cell proliferation ratio was decreased with positive PCNA counts. In the presence of matrices, the cell proliferation ratio decreased at low VPA concentrations compared with the ratio obtained in the absence of these ECMs. On the other hand, VPA promoted osteoblastic differentiation in the presence of type I collagen. These findings indicate that for undifferentiated mesenchymal cells, VPA promotes a decrease in the cell proliferation rate in the presence of ECMs and promotes osteoblastic differentiation, both of which could provide insight into additional mechanisms of osteoblastic cell differentiation caused by VPA.
A Model for NAD(P)H:Quinoneoxidoreductase 1 (NQO1) Targeted Individualized Cancer Chemotherapy.
Begleiter A, El-Gabalawy N, Lange L … +3 more , Leith MK, Guziec LJ, Guziec FS
Drug Target Insights · 2009 · PMID 21904446 · Full text
NQO1 (NAD(P)H:quinoneoxidoreductase 1) is a reductive enzyme that is an important activator of bioreductive antitumor agents. NQO1 activity varies in individual tumors but is generally higher in tumor cells than in norma...
NQO1 (NAD(P)H:quinoneoxidoreductase 1) is a reductive enzyme that is an important activator of bioreductive antitumor agents. NQO1 activity varies in individual tumors but is generally higher in tumor cells than in normal cells. NQO1 has been used as a target for tumor specific drug development. We investigated a series of bioreductive benzoquinone mustard analogs as a model for NQO1 targeted individualized cancer chemotherapy. We compared the tumor cell growth inhibitory activity of benzoquinone mustard analogs with sterically bulky groups of different size and placed at different positions on the benzoquinone ring, using tumor cell lines with different levels of NQO1. We demonstrated that functional groups of different steric size could be used to produce a series of bioreductive antitumor agents that were activated by different levels of NQO1 in tumor cells. This series of drugs could then be used to target cells with specific levels of NQO1 for growth inhibition and to avoid damage to normal cells, like bone marrow cells, that have low levels of NQO1. This approach could be used to develop new bioreductive antitumor agents for NQO1 targeted individualized cancer chemotherapy.
Effects of ascorbic Acid, alpha-tocopherol and allopurinol on ischemia-reperfusion injury in rabbit skeletal muscle: an experimental study.
Erkut B, Özyazıcıoğlu A, Karapolat BS … +5 more , Koçoğulları CU, Keles S, Ateş A, Gundogdu C, Kocak H
Drug Target Insights · 2007 · PMID 21901079
PURPOSE: Ischemia reperfusion injury to skeletal muscle, following an acute arterial occlusion is important cause of morbidity and mortality. The aim of the present study was to determine and evaluate the effects of asco...
PURPOSE: Ischemia reperfusion injury to skeletal muscle, following an acute arterial occlusion is important cause of morbidity and mortality. The aim of the present study was to determine and evaluate the effects of ascorbic acide, alpha-tocopherol and allopurinol on ischemia reperfusion injury in rabbit skeletal muscle. METHODS: Forty-eight New Zealand white rabbits, all male, weighing between 2.5 to 3.0 (mean 2.8) kg, were used in the study. They were separated into four groups. Group I was the control group without any drugs. The other groups were treatment groups (groups II, III, and IV). Group II rabbits administrated 50 mg/kg ascorbic acide and 100 mg/kg alpha-tocopherol 3 days prior to ischemia, group III rabbits received 50 mg/kg allopurinol 2 days prior to ischemia, and group IV rabbits were administrated both 50 mg/kg ascorbic acide, 100 mg/kg alpha-tocopherol 3 days prior to ischemia and 50 mg/kg allopurinol 2 days prior to ischemia. Two hours ischemia and 2 hours reperfusion were underwent to the treatment groups. At the end of the reperfusion periods, muscle samples were taken from rectus femoris muscle for determination of superoxide dismutase, catalase and glutathione peroxidase activities as antioxidant enzymes, and malondialdehyde as an indicator of lipid peroxidation and xanthine oxidase levels as source hydroxyl radical. Besides, histopathological changes (edema, inflammation, ring formation and splitting formation) were evaluated in the muscle specimens. RESULTS: In the treatment groups; superoxide dismutase (U/mgprotein), catalase (U/mgprotein), and glutathione peroxidase (U/mgprotein) levels increased, malondialdehyde (nmol/mgprotein) and xanthine oksidase (mU/mgprotein) levels decreased compared to control I ( p < 0.05). Increase of superoxide dismutase, catalase, and glutathione peroxidase levels were the highest and decrease of malondialdehyde and xanthine oxidase levels were the highest in group IV compared to groups II and III, but no significant as statistically. Also amount of cellular injury in group II, III, and IV were lower than group I. CONCLUSIONS: Antioxidant medication may help lowering ischemia reperfusion injury. In our study, all drug medications are shown to be able to have an effective role for preventing ischemia reperfusion injury. Moreover, ascorbic acide + alpha-tocopherol + allopurinol group (group IV) may have a beneficial effect to decrease the local and systemic damage due to ischemia-reperfusion injury.
Platelet-derived growth factor as a therapeutic target for systemic autoimmune diseases.
Kameda H, Suzuki M, Takeuchi T
Drug Target Insights · 2007 · PMID 21901078
Some systemic rheumatic diseases and disorders, especially fibrotic and vascular disorders, are often refractory to corticosteroid therapy. Recently, ever accumulating evidence suggests that platelet-derived growth facto...
Some systemic rheumatic diseases and disorders, especially fibrotic and vascular disorders, are often refractory to corticosteroid therapy. Recently, ever accumulating evidence suggests that platelet-derived growth factor (PDGF) is involved in those refractory diseases. Imatinib mesylate inhibits the activation of PDGF receptor as well as c-Abl, Bcr-Abl and c-Kit tyrosine kinases. It has therefore been widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib effectively suppresses the activation and proliferation of fibroblasts, mesangial cells and smooth muscle cells both in vitro and in vivo. Additionally, it has recently been reported that some patients with rheumatoid arthritis or idiopathic pulmonary arterial hypertension demonstrated a good clinical response to imatinib therapy. Imatinib may therefore overcome the limitations of current therapeutic strategy with corticosteroids and immunosuppressive agents for refractory diseases, such as systemic sclerosis and interstitial lung diseases, without clinical intolerability.
New insights into the understanding of gastrointestinal dysmotility.
Ohlsson B, Janciauskiene S
Drug Target Insights · 2007 · PMID 21901077
Our understanding of the physiology of digestion, absorption, secretion, and motility in the gastrointestinal tract has improved immensely. Today it is well established that the gross functions of the gastrointestinal tr...
Our understanding of the physiology of digestion, absorption, secretion, and motility in the gastrointestinal tract has improved immensely. Today it is well established that the gross functions of the gastrointestinal tract depend on the coordination between the muscles, nerves and hormones. The enteric nervous system (ENS) is involved in most of the physiological and pathophysiological processes in the gastrointestinal tract. Therefore, clinical and experimental studies on the ENS provide the basis for a better understanding of the mechanisms involved in gastrointestinal disorders and promote the development of therapeutic options. This review outlines some of the current views on the role of the ENS and its related hormones in gastrointestinal motility.
Effect of live Salmonella Ty21a in dextran sulfate sodium-induced colitis.
Nysœter G, Erichsen K, Milde AM … +3 more , Colás E, Kristoffersen E, Berstad A
Drug Target Insights · 2007 · PMID 21901076 · Full text
BACKGROUND: Intestinal microbiota seems to play an essential role in the development of inflammatory bowel diseases (IBD). We hypothesised that an oral vaccine based on live Salmonella typhi would be well tolerated and c...
BACKGROUND: Intestinal microbiota seems to play an essential role in the development of inflammatory bowel diseases (IBD). We hypothesised that an oral vaccine based on live Salmonella typhi would be well tolerated and could even attenuate dextran sulfate sodium (DSS) induced colitis in rats, an animal model of IBD. METHODS: Nine male Wistar rats was used for an initial tolerance study, in which we used 3 dose-levels of Salmonella Ty21a, 0.5 × 10(9), 1 × 10(9), and 2 × 10(9)CFU, each dose being tested in 3 rats. Four treatment groups consisting of 8 male Wistar rats per group: 1) control group given standard food and water, 2) control group given four daily administrations of Salmonella Ty21a 1 × 10(9) CFU, 3) water with 5% DSS the last 7 days, 4) four daily administrations of Salmonella Ty21a before water with 5% DSS the last 7 days. The Salmonella Ty21a was administered by gastric gavage on day 1, 3, 5 and 16, while DSS was given with the drinking water from day 15 to 22. The animals were sacrificed and colonic tissue removed for analysis 22 days after gavage of the first vaccine dose. RESULTS: The animals in the tolerance study got no signs of disease. In the treatment study, all animals receiving DSS had histologic indications of colitis, particularly in the distal part of the colon. Administration of Salmonella Ty21a had no significant effect on crypt and inflammation scores (p > 0.05). CONCLUSION: Gastric administration of live vaccine strain Salmonella Ty21a was well tolerated, but did not provide any significant protection against development of DSS induced colitis in rats.
Use and safety of anthroposophic medications for acute respiratory and ear infections: a prospective cohort study.
Hamre HJ, Glockmann A, Fischer M … +3 more , Riley DS, Baars E, Kiene H
Drug Target Insights · 2007 · PMID 21901075
OBJECTIVE: Anthroposophic medications (AMED) are widely used, but safety data on AMED from large prospective studies are sparse. The objective of this analysis was to determine the frequency of adverse drug reactions (AD...
OBJECTIVE: Anthroposophic medications (AMED) are widely used, but safety data on AMED from large prospective studies are sparse. The objective of this analysis was to determine the frequency of adverse drug reactions (ADR) to AMED in outpatients using AMED for acute respiratory and ear infections. METHODS: A prospective four-week observational cohort study was conducted in 21 primary care practices in Europe and the U.S.A. The cohort comprised 715 consecutive outpatients aged ≥1 month, treated by anthroposophic physicians for acute otitis and respiratory infections. Physicians' prescription data and patient reports of adverse events were analyzed. Main outcome measures were use of AMED and ADR to AMED. RESULTS: two patients had confirmed ADR to AMED: 1) swelling and redness at the injection site after subcutaneous injections of Prunus spinosa 5%, 2) sleeplessness after intake of Pneumodoron(®) 2 liquid. These ADR lasted one and two days respectively; both subsided after dose reduction; none were unexpected; none were serious. The frequency of confirmed ADR to AMED was 0.61% (2/327) of all different AMED used, 0.28% (2/715) of patients, and 0.004% (3/73,443) of applications. CONCLUSION: In this prospective study, anthroposophic medications used by primary care patients with acute respiratory or ear infections were well tolerated.
Targeted brain tumor treatment-current perspectives.
Ningaraj NS, Salimath BP, Sankpal UT … +2 more , Perera R, Vats T
Drug Target Insights · 2007 · PMID 21901074
Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have...
Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (K(Ca)) channels, and high grade glioma express specific K(Ca) channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.
Delivery systems for in vivo use of nucleic Acid drugs.
Resende RR, Torres HA, Yuahasi KK … +2 more , P M, H U
Drug Target Insights · 2007 · PMID 21901073
The notorious biotechnological advance of the last few decades has allowed the development of experimental methods for understanding molecular mechanisms of genes and new therapeutic approaches. Gene therapy is maturing...
The notorious biotechnological advance of the last few decades has allowed the development of experimental methods for understanding molecular mechanisms of genes and new therapeutic approaches. Gene therapy is maturing into a viable, practical method with the potential to cure a variety of human illnesses. Some nucleic-acid-based drugs are now available for controlling the progression of genetic diseases by inhibiting gene expression or the activity of their gene products. New therapeutic strategies employ a wide range of molecular tools such as bacterial plasmids containing transgenic inserts, RNA interference and aptamers. A nucleic-acid based constitution confers a lower immunogenic potential and as result of the high stringency selection of large molecular variety, these drugs have high affinity and selectivity for their targets. However, nucleic acids have poor biostability thus requiring chemical modifications and delivery systems to maintain their activity and ease their cellular internalization. This review discusses some of the mechanisms of action and the application of therapies based on nucleic acids such as aptamers and RNA interference as well as platforms for cellular uptake and intracellular delivery of therapeutic oligonucleotides and their trade-offs.
Targeting human immunodeficiency virus type 1 assembly, maturation and budding.
Wapling J, Srivastava S, Shehu-Xhilaga M … +1 more , Tachedjian G
Drug Target Insights · 2007 · PMID 21901072
The targets for licensed drugs used for the treatment of human immunodeficiency virus type 1 (HIV-1) are confined to the viral reverse transcriptase (RT), protease (PR), and the gp41 transmembrane protein (TM). While cur...
The targets for licensed drugs used for the treatment of human immunodeficiency virus type 1 (HIV-1) are confined to the viral reverse transcriptase (RT), protease (PR), and the gp41 transmembrane protein (TM). While currently approved drugs are effective in controlling HIV-1 infections, new drug targets and agents are needed due to the eventual emergence of drug resistant strains and drug toxicity. Our increased understanding of the virus life-cycle and how the virus interacts with the host cell has unveiled novel mechanisms for blocking HIV-1 replication. This review focuses on inhibitors that target the late stages of virus replication including the synthesis and trafficking of the viral polyproteins, viral assembly, maturation and budding. Novel approaches to blocking the oligomerization of viral enzymes and the interactions between viral proteins and host cell factors, including their feasibility as drug targets, are discussed.
Polymeric nanoparticles, nanospheres and nanocapsules, for cutaneous applications.
Guterres SS, Alves MP, Pohlmann AR
Drug Target Insights · 2007 · PMID 21901071
This review presents an overview about pharmaceutical and cosmetic topical products containing polymeric nanoparticles (nanospheres and nanocapsules), reporting the main preparation and characterization methods and the s...
This review presents an overview about pharmaceutical and cosmetic topical products containing polymeric nanoparticles (nanospheres and nanocapsules), reporting the main preparation and characterization methods and the studies of penetration and transport of substances through the skin. The penetration and transport extent of those systems through the skin depends on the ingredients chemical composition, on the encapsulation mechanism influencing the drug release, on the size of nanoparticles and on the viscosity of the formulations. The polymeric nanoparticles are able to modify the activity of drugs, delay and control the drug release, and increase the drug adhesivity or its time of permanence in the skin. Briefly, the nanoparticles can be useful as reservoirs of lipophilic drugs to deliver them in the stratum corneum becoming an important strategy to control their permeation into the skin.
Trypanothione reductase: a viable chemotherapeutic target for antitrypanosomal and antileishmanial drug design.
Khan MO
Drug Target Insights · 2007 · PMID 21901070
Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for ration...
Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The process of designing selective inhibitors for the enzyme trypanothione reductase has been discussed. An overview of the different chemical classes of inhibitors of trypanothione reductase with their inhibitory activities against the parasites and their prospects as future chemotherapeutic agents are briefly revealed.
The relationship of arginine deprivation, argininosuccinate synthetase and cell death in melanoma.
Savaraj N, Wu C, Kuo MT … +5 more , You M, Wangpaichitr M, Robles C, Spector S, Feun L
Drug Target Insights · 2007 · PMID 21901069
It has been shown that melanoma cells do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. Depleting arginine using pegylated arginine deiminase (ADI-PEG20) r...
It has been shown that melanoma cells do not express argininosuccinate synthetase (ASS) and therefore are unable to synthesize arginine from citrulline. Depleting arginine using pegylated arginine deiminase (ADI-PEG20) results in cell death in melanoma but not normal cells. This concept was translated into clinical trial and responses were seen. However, induction of ASS expression does occur which results in resistance to ADI-PEG20. We have used 4 melanoma cell lines to study factors which may govern ASS expression. Although these 4 melanoma cell lines do not express ASS protein or mRNA as detected by both immunoblot and northernblot analysis, ASS protein can be induced after these cells are grown in the presence of ADI-PEG20, but again repressed after replenishing arginine in the media. The levels of induction are different and one cell line could not be induced. Interestingly, a melanoma cell line with the highest level of induction could also be made resistant to ADI-PEG20. This resistant line possesses high levels of ASS mRNA and protein expression which cannot be repressed with arginine. Our study indicates that ASS expression in melanoma cells is complex and governed by biochemical parameters which are different among melanoma cells.
Endothelial dysfunction, erectile dysfunction and phosphodiesterase 5 inhibitors. An update of the current data and future perspectives.
Konstantinopoulos A, Giannitsas K, Raptis S … +1 more , Perimenis P
Drug Target Insights · 2007 · PMID 21901068
Endothelial dysfunction is a pathological entity that multiply affects the health status. Erectile dysfunction is being recognized as a condition that is strongly interrelated with endothelial dysfunction, being a vascul...
Endothelial dysfunction is a pathological entity that multiply affects the health status. Erectile dysfunction is being recognized as a condition that is strongly interrelated with endothelial dysfunction, being a vascular event itself. Oral pharmacotherapy for erectile dysfunction has provided us with a new armamentarium on this condition. Phosphodiesterase 5 inhibitors have been investigated and proved useful in clinical practice for erectile dysfunction but in addition to this, the results seem promising of a beneficial effect on endothelial dysfunction, as well.
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