6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2019/10/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Repurposing of known drugs for leishmaniasis treatment using bioinformatic predictions, in vitro validations and pharmacokinetic simulations.

J Comput Aided Mol Des. 2019 Oct 14;:

Authors: Bustamante C, Ochoa R, Asela C, Muskus C

Abstract
Leishmaniasis is a neglected tropical disease caused by Leishmania parasites and is associated to more than 1.3 million cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonials, pentamidine, miltefosine, and amphotericin B. However, all are associated with a wide range of adverse effects and contraindications, as well as resistance from the parasite. In the present study, we looked for pharmacological alternatives to treat leishmaniasis, with a focus on drug repurposing. This was done by detecting potential homologs between proteins targeted by approved drugs and proteins of the parasite. The proteins were analyzed using an interaction network, and the drugs were subjected to in vitro evaluations and pharmacokinetics simulations to compare probable plasma concentrations with the effective concentrations detected experimentally. This strategy yielded a list of 33 drugs with potential anti-Leishmania activity, and more than 80 possible protein targets in the parasite. From the drugs tested, two reported high in vitro activity (perphenazine EC50 = 1.2 µg/mL and rifabutin EC50 = 8.5 µg/mL). These results allowed us to propose these drugs as candidates for further in vivo studies and evaluations of the effectiveness on their topical forms.

PMID: 31612362 [PubMed - as supplied by publisher]

Dihydroartemisinin up-regulates VE-cadherin expression in human renal glomerular endothelial cells.

J Cell Mol Med. 2018 03;22(3):2028-2032

Authors: Li L, Chen X, Dong F, Liu Q, Zhang C, Xu D, Allen TD, Liu J

Abstract
The antimalarial agent dihydroartemisinin (DHA) has been shown to be anti-inflammatory. In this study, we found that DHA increased the expression of the junctional protein vascular endothelial (VE)-cadherin in human renal glomerular endothelial cells. In addition, DHA inhibited TGF-β RI-Smad2/3 signalling and its downstream effectors SNAIL and SLUG, which repress VE-cadherin gene transcription. Correspondingly, DHA decreased the binding of SNAIL and SLUG to the VE-cadherin promoter. Together, our results suggest an effect of DHA in regulating glomerular permeability by elevation of VE-cadherin expression.

PMID: 29193726 [PubMed - indexed for MEDLINE]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2019/10/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Adapalene inhibits ovarian cancer ES-2 cells growth by targeting glutamic-oxaloacetic transaminase 1.

Bioorg Chem. 2019 Sep 26;93:103315

Authors: Wang Q, Zhang Q, Luan S, Yang K, Zheng M, Li K, Chen L, Li H

Abstract
Glutamic-oxaloacetic transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements for sustained proliferation. As such, the GOT1 inhibitor may provide a new strategy for the treatment of various cancers. Adapalene has been approved by FDA for the treatment of acne, pimples and pustules, and it may also contribute to the adjunctive therapy for advanced stages of liver and colorectal cancers. In this work, we first examined the enzyme inhibition of over 500 compounds against GOT1 in vitro. As a result, Adapalene effectively inhibited GOT1 enzyme in a non-competitive manner. MST and DARTS assay further confirmed the high affinity between Adapalene and GOT1. Furthermore, the growth and migration of ovarian cancer ES-2 cells were obviously inhibited by the treatment of Adapalene. And it induced the apoptosis of ES-2 cells according to Western blot and Hoechst 33258 straining. In addition, molecular docking demonstrated that Adapalene coordinated in an allosteric site of GOT1 with low binding energy. Furthermore, knockdown of GOT1 in ES-2 cells decreased their anti-proliferative sensitivity to Adapalene. Together, our data strongly suggest Adapalene, as a GOT1 inhibitor, could be regarded as a potential drug candidate for ovarian cancer therapy.

PMID: 31605927 [PubMed - as supplied by publisher]

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Cancer. 2019 01 01;125(1):18-44

Authors: Jeter JM, Bowles TL, Curiel-Lewandrowski C, Swetter SM, Filipp FV, Abdel-Malek ZA, Geskin LJ, Brewer JD, Arbiser JL, Gershenwald JE, Chu EY, Kirkwood JM, Box NF, Funchain P, Fisher DE, Kendra KL, Marghoob AA, Chen SC, Ming ME, Albertini MR, Vetto JT, Margolin KA, Pagoto SL, Hay JL, Grossman D, Ellis DL, Kashani-Sabet M, Mangold AR, Markovic SN, Nelson KC, Powers JG, Robinson JK, Sahni D, Sekulic A, Sondak VK, Wei ML, Zager JS, Dellavalle RP, Thompson JA, Weinstock MA, Leachman SA, Cassidy PB

Abstract
Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

PMID: 30281145 [PubMed - indexed for MEDLINE]

Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria.

Sci Transl Med. 2018 09 19;10(459):

Authors: Urquiza P, Laín A, Sanz-Parra A, Moreno J, Bernardo-Seisdedos G, Dubus P, González E, Gutiérrez-de-Juan V, García S, Eraña H, San Juan I, Macías I, Ben Bdira F, Pluta P, Ortega G, Oyarzábal J, González-Muñiz R, Rodríguez-Cuesta J, Anguita J, Díez E, Blouin JM, de Verneuil H, Mato JM, Richard E, Falcón-Pérez JM, Castilla J, Millet O

Abstract
Congenital erythropoietic porphyria is a rare autosomal recessive disease produced by deficient activity of uroporphyrinogen III synthase, the fourth enzyme in the heme biosynthetic pathway. The disease affects many organs, can be life-threatening, and currently lacks curative treatments. Inherited mutations most commonly reduce the enzyme's stability, altering its homeostasis and ultimately blunting intracellular heme production. This results in uroporphyrin by-product accumulation in the body, aggravating associated pathological symptoms such as skin photosensitivity and disfiguring phototoxic cutaneous lesions. We demonstrated that the synthetic marketed antifungal ciclopirox binds to the enzyme, stabilizing it. Ciclopirox targeted the enzyme at an allosteric site distant from the active center and did not affect the enzyme's catalytic role. The drug restored enzymatic activity in vitro and ex vivo and was able to alleviate most clinical symptoms of congenital erythropoietic porphyria in a genetic mouse model of the disease at subtoxic concentrations. Our findings establish a possible line of therapeutic intervention against congenital erythropoietic porphyria, which is potentially applicable to most of deleterious missense mutations causing this devastating disease.

PMID: 30232228 [PubMed - indexed for MEDLINE]

Repurposing drugs to target the malaria parasite unfolding protein response.

Sci Rep. 2018 07 09;8(1):10333

Authors: Chen Y, Murillo-Solano C, Kirkpatrick MG, Antoshchenko T, Park HW, Pizarro JC

Abstract
Drug resistant Plasmodium falciparum parasites represent a major obstacle in our efforts to control malaria, a deadly vector borne infectious disease. This situation creates an urgent need to find and validate new drug targets to contain the spread of the disease. Several genes associated with the unfolded protein response (UPR) including Glucose-regulated Protein 78 kDa (GRP78, also known as BiP) have been deemed potential drug targets. We explored the drug target potential of GRP78, a molecular chaperone that is a regulator of the UPR, for the treatment of P. falciparum parasite infection. By screening repurposed chaperone inhibitors that are anticancer agents, we showed that GRP78 inhibition is lethal to drug-sensitive and -resistant P. falciparum parasite strains in vitro. We correlated the antiplasmodial activity of the inhibitors with their ability to bind the malaria chaperone, by characterizing their binding to recombinant parasite GRP78. Furthermore, we determined the crystal structure of the ATP binding domain of P. falciparum GRP78 with ADP and identified structural features unique to the parasite. These data suggest that P. falciparum GRP78 can be a valid drug target and that its structural differences to human GRP78 emphasize potential to generate parasite specific compounds.

PMID: 29985421 [PubMed - indexed for MEDLINE]

PDE3A inhibitor anagrelide activates death signaling pathway genes and synergizes with cell death-inducing cytokines to selectively inhibit cancer cell growth.

Am J Cancer Res. 2019;9(9):1905-1921

Authors: An R, Liu J, He J, Wang F, Zhang Q, Yu Q

Abstract
We performed a drug repurposing screening of a US Food and Drug Administration (FDA)-approved drug compound library and identified Anagrelide (ANA), a known phosphodiesterase 3A (PDE3A) inhibitor, that selectively and potently inhibited the growth of cancer cells. However, inactivation of PDE3A or knocking-down its gene expression did not inhibit cancer cell growth. It was the interaction of ANA with PDE3A that created a new function of PDE3A to alter the activities of another unknown function protein SLFN12 to cause the inhibition of cancer cell growth. The expressions of both PDE3A and SLFN12 were required for ANA to inhibit cancer cell growth. Depletion of PDE3A or SLFN12 led to ANA resistance. Furthermore, the effects of ANA on different cancer cells were different depending on the expression levels of PDE3A and SLFN12, causing G0/G1 cell cycle arrest in the cells expressing lower levels of SLFN12, but apoptosis in the cells expressing higher levels of the two proteins. Further investigation into the molecular mechanisms of the ANA-induced cell cycle arrest and apoptosis identified a set of cell cycle and apoptosis-related genes whose expressions were altered by ANA treatment. ANA also synergized with the cell death-inducing cytokines IFN-α, IFN-γ, TNF-α, or TRAIL, which regulated the same set of genes as ANA did, to induce apoptosis of the cancer cells. Our study uncovered new activities, functions, and mechanisms of ANA and SLFN12 and provided a diagnosis method to precisely use ANA as an anti-cancer drug. It also revealed PDE3A and SLFN12 as new anti-cancer drug targets for developing novel anti-cancer therapies.

PMID: 31598394 [PubMed]

Naturally-occurring polymorphisms in QcrB are responsible for resistance to Telacebec in Mycobacterium abscessus.

ACS Infect Dis. 2019 Oct 10;:

Authors: Sorayah R, Manimekalai MSS, Shin SJ, Koh WJ, Grüber G, Pethe K

Abstract
Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the anti-tuberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the sub-unit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB are responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphism sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.

PMID: 31599569 [PubMed - as supplied by publisher]

In vitro antileishmanial activity of ravuconazole, a triazole antifungal drug, as a potential treatment for leishmaniasis.

J Antimicrob Chemother. 2018 09 01;73(9):2360-2373

Authors: Teixeira de Macedo Silva S, Visbal G, Lima Prado Godinho J, Urbina JA, de Souza W, Cola Fernandes Rodrigues J

Abstract
Objectives: Leishmaniasis, one of the most significant neglected diseases around the world, is caused by protozoan parasites of the Leishmania genus. Nowadays, the available aetiological treatments for leishmaniasis have variable effectiveness and several problems such as serious side effects, toxicity, high cost and an increasing number of resistance cases. Thus, there is an urgent need for safe, oral and cost-effective drugs for leishmaniases. Previously, our group has shown the effect of the ergosterol biosynthesis inhibitors on Leishmania amazonensis. Herein, we showed the effect of ravuconazole against L. amazonensis; ravuconazole is a second-generation triazole antifungal drug that has good bioavailability after oral administration and a long terminal half-life in humans, a broad activity spectrum, high effectiveness in treatment of mycosis and negligible side effects.
Methods: Several methodologies were used: cell culture, fluorescence and electron microscopy, high-resolution capillary GC coupled with MS, fluorimetry and flow cytometry.
Results: Our results showed that ravuconazole was able to inhibit the proliferation of L. amazonensis promastigotes and intracellular amastigotes in vitro, with single-digit to sub-micromolar IC50 values, causing several alterations in the morphology, ultrastructure, cell viability and physiology of the parasites. The mitochondrion was significantly affected by the treatment, resulting in a collapse of the mitochondrial transmembrane potential that consequently led to inhibition of ATP production, combined with an increase in reactive oxygen species and mitochondrial superoxide production; by transmission electron microscopy, the organelle displayed a completely altered ultrastructure. The treatment changed the lipid profile, showing a profound depletion of the 14-desmethyl endogenous sterol pool.
Conclusions: These results suggest that ravuconazole could be an alternative option for the treatment of leishmaniasis.

PMID: 29982734 [PubMed - indexed for MEDLINE]

Carbonic anhydrase inhibition and the management of glaucoma: a literature and patent review 2013-2019.

Expert Opin Ther Pat. 2019 Oct 09;:

Authors: Supuran CT, Altamimi ASA, Carta F

Abstract
Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme Carbonic Anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: The present review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for i) new CAI moieties and ii) classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so called "old drugs" will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.

PMID: 31596641 [PubMed - as supplied by publisher]

Sofosbuvir inhibits yellow fever virus in vitro and in patients with acute liver failure.

Ann Hepatol. 2019 Sep 25;:

Authors: Mendes ÉA, Pilger DRB, Santos Nastri ACS, Malta FM, Pascoalino BDS, Carneiro D'Albuquerque LA, Balan A, Freitas LHG, Durigon EL, Carrilho FJ, Rebello Pinho JR

Abstract
INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) are very efficient in inhibiting hepatitis C virus and might be used to treat infections caused by other flaviviruses whose worldwide detection has recently increased. The aim of this study was to verify the efficacy of DAAs in inhibiting yellow fever virus (YFV) by using drug repositioning (a methodology applied in the pharmaceutical industry to identify new uses for approved drugs).
MATERIALS AND METHODS: Three DAAs were evaluated: daclatasvir, sofosbuvir and ledipasvir or their combinations. For in vitro assays, the drugs were diluted in 100% dimethyl sulfoxide. Vaccine strain 17D and a 17D strain expressing the reporter fluorescent protein were used in the assays. A fast and reliable cell-based screening assay using Vero cells or Huh-7 cells (a hepatocyte-derived carcinoma ell line) was carried out. Two patients who acquired yellow fever virus with acute liver failure were treated with sofosbuvir for one week as a compassionate use.
RESULTS: Using a high-content screening assay, we verified that sofosbuvir presented the best antiviral activity against YFV. Moreover, after an off-label treatment with sofosbuvir, the two female patients diagnosed with yellow fever infection displayed a reduction in blood viremia and an improvement in the course of the disease, which was observed in the laboratory medical parameters related to disease evolution.
CONCLUSIONS: Sofosbuvir may be used as an option for treatment against YFV until other drugs are identified and approved for human use. These results offer insights into the role of nonstructural protein 5 (NS5) in YFV inhibition and suggest that nonstructural proteins may be explored as drug targets for YFV treatment.

PMID: 31594756 [PubMed - as supplied by publisher]

iATC-NRAKEL: An efficient multi-label classifier for recognizing anatomical therapeutic chemical (ATC) classes of drugs.

Bioinformatics. 2019 Oct 08;:

Authors: Zhou JP, Chen L, Guo ZH

Abstract
MOTIVATION: The anatomical therapeutic chemical (ATC) classification system plays an increasingly important role in drug repositioning and discovery. The correct identification of classes in each level of such system that a given drug may belong to is an essential problem. Several multi-label classifiers have been proposed in this regard. Although they provided satisfactory performance, the feature extraction procedures were still rough. More refined features may further improve the predicted quality.
RESULTS: In this paper, we provide a novel multi-label classifier, called iATC-NRAKEL, to predict drug ATC classes in the first level. To obtain more informative drug features, we employed the drug association information in STITCH and KEGG, which was organized by seven drug networks. The powerful network embedding algorithm, Mashup, was adopted to extract informative drug features. The obtained features were fed into the RAndom k-labELsets (RAKEL) algorithm with support vector machine as the basic classification algorithm to construct the classifier. The tenfold cross-validation of the benchmark dataset with 3,883 drugs showed that the accuracy and absolute true were 76.56% and 74.51%, respectively. The comparison results indicated that iATC-NRAKEL was much superior to all previous reported classifiers. Finally, the contribution of each network was analyzed.
AVAILABILITY: The codes of iATC-NRAKEL are available at https://github.com/zhou256/iATC-NRAKEL.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 31593226 [PubMed - as supplied by publisher]

A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma.

Oncogene. 2019 Oct 07;:

Authors: Salcher S, Spoden G, Hagenbuchner J, Führer S, Kaserer T, Tollinger M, Huber-Cantonati P, Gruber T, Schuster D, Gust R, Zwierzina H, Müller T, Kiechl-Kohlendorfer U, Ausserlechner MJ, Obexer P

Abstract
The transcription factor FOXO3 has been associated in different tumor entities with hallmarks of cancer, including metastasis, tumor angiogenesis, maintenance of tumor-initiating stem cells, and drug resistance. In neuroblastoma (NB), we recently demonstrated that nuclear FOXO3 promotes tumor angiogenesis in vivo and chemoresistance in vitro. Hence, inhibiting the transcriptional activity of FOXO3 is a promising therapeutic strategy. However, as no FOXO3 inhibitor is clinically available to date, we used a medium-throughput fluorescence polarization assay (FPA) screening in a drug-repositioning approach to identify compounds that bind to the FOXO3-DNA-binding-domain (DBD). Carbenoxolone (CBX), a glycyrrhetinic acid derivative, was identified as a potential FOXO3-inhibitory compound that binds to the FOXO3-DBD with a binding affinity of 19 µM. Specific interaction of CBX with the FOXO3-DBD was validated by fluorescence-based electrophoretic mobility shift assay (FAM-EMSA). CBX inhibits the transcriptional activity of FOXO3 target genes, as determined by chromatin immunoprecipitation (ChIP), DEPP-, and BIM promoter reporter assays, and real-time RT-PCR analyses. In high-stage NB cells with functional TP53, FOXO3 triggers the expression of SESN3, which increases chemoprotection and cell survival. Importantly, FOXO3 inhibition by CBX treatment at pharmacologically relevant concentrations efficiently repressed FOXO3-mediated SESN3 expression and clonogenic survival and sensitized high-stage NB cells to chemotherapy in a 2D and 3D culture model. Thus, CBX might be a promising novel candidate for the treatment of therapy-resistant high-stage NB and other "FOXO-resistant" cancers.

PMID: 31591479 [PubMed - as supplied by publisher]

Targeting bacterial antioxidant systems for antibiotics development.

Curr Med Chem. 2019 Oct 07;:

Authors: Ren X, Zou L, Holmgren A

Abstract
The emergence of multidrug-resistant bacteria has become an urgent issue in modern medicine which requires novel strategies to develop antibiotics. Recent studies have supported the hypothesis that antibiotic-induced bacterial cell death is mediated by reactive oxygen species (ROS). The hypothesis also highlighted the importance of antioxidant systems the defense mechanism which contribute to antibiotic resistance. Thioredoxin and glutathione systems are the two major thiol-dependent systems not only provide antioxidant capacity but also participate in various biological events in bacteria, such as DNA synthesis and protein folding. The biological importance makes them promising targets for novel antibiotics development. Based on the idea, ebselen and auranofin, two bacterial thioredoxin reductase inhibitors, have been found to inhibit the growth of bacteria lacking the GSH efficiently. A recent study combining ebselen and silver exhibited a strong synergistic effect against multidrug-resistant (MDR) Gram-negative bacteria which possess both thioredoxin and glutathione systems. These drug-repurposing studies are promising for quick clinical usage due to their well-known profile.

PMID: 31589114 [PubMed - as supplied by publisher]

High-throughput drug screening using the Ebola virus transcription- and replication-competent virus-like particle system.

Antiviral Res. 2018 10;158:226-237

Authors: Lee N, Shum D, König A, Kim H, Heo J, Min S, Lee J, Ko Y, Choi I, Lee H, Radu C, Hoenen T, Min JY, Windisch MP

Abstract
The massive epidemic of Ebola virus disease (EVD) in West Africa, followed in recent months by two outbreaks in the Democratic Republic of the Congo, underline the importance of this severe disease. Because Ebola virus (EBOV) must be manipulated under biosafety level 4 (BSL4) containment, the discovery and development of virus-specific therapies have been hampered. Recently, a transient transfection-based transcription- and replication competent virus-like particle (trVLP) system was described, enabling modeling of the entire EBOV life cycle under BSL2 conditions. Using this system, we optimized the condition for bulk co-transfection of multiple plasmids, developed a luciferase reporter-based assay in 384-well microtiter plates, and performed a high-throughput screening (HTS) campaign of an 8,354-compound collection consisting of U.S. Food & Drug Administration (FDA) -approved drugs, bioactives, kinase inhibitors, and natural products in duplicates. The HTS achieved a good signal-to-background ratio with a low percent coefficient of variation resulting in Z' = 0.7, and data points were reproducible with R2 = 0.89, indicative of a robust assay. After applying stringent hit selection criteria of ≥70% EBOV trVLP inhibition and ≥70% cell viability, 381 hits were selected targeting early, entry, and replication steps and 49 hits targeting late, maturation, and secretion steps in the viral life cycle. Of the total 430 hits, 220 were confirmed by dose-response analysis in the primary HTS assay. They were subsequently triaged by time-of-addition assays, then clustered and ranked according to their chemical structures, biological functions, therapeutic index, and maximum inhibition. Several novel drugs have been identified to very efficiently inhibit EBOV. Interestingly, most showed pharmacological activity in treatments for central nervous system-related diseases. We developed and screened an HTS assay using the novel EBOV trVLP system. Newly identified inhibitors are useful tools to study the poorly understood EBOV life cycle. In addition, they also provide opportunities to either repurpose FDA-approved drugs or develop novel viral interventions to combat EVD.

PMID: 30149038 [PubMed - indexed for MEDLINE]

Oral anticoagulant use in cardiovascular disorders: a perspective on present and potential indications for rivaroxaban.

Curr Med Res Opin. 2018 11;34(11):1945-1957

Authors: Camm AJ, Fox KAA

Abstract
BACKGROUND: Four non-vitamin-K-antagonist oral anticoagulants (NOACs) have been approved for use in various cardiovascular indications. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban and rivaroxaban are now increasingly used in clinical practice. For some of these agents, available data from real-world studies support the efficacy and safety data in phase III clinical trials.
OBJECTIVES: This review aims to summarize the current status of trials and observational studies of oral anticoagulant use over the spectrum of cardiovascular disorders (excluding venous thrombosis), provide a reference source beyond stroke prevention for atrial fibrillation (AF) and examine the potential for novel applications in the cardiovascular field.
METHODS: We searched the recent literature for data on completed and upcoming trials of oral anticoagulants with a particular focus on rivaroxaban.
RESULTS: Recent data in specific patient subgroups, such as patients with AF undergoing catheter ablation or cardioversion, have led to an extended approval for rivaroxaban, whereas the other NOACs have ongoing or recently completed trials in this setting. However, there are unmet medical needs for several arterial thromboembolic-related conditions, including patients with: AF and acute coronary syndrome, AF and coronary artery disease undergoing elective percutaneous coronary intervention, coronary artery disease and peripheral artery disease, implanted cardiac devices, and embolic stroke of unknown source.
CONCLUSION: NOACs may provide alternative treatment options in areas of unmet need, and numerous studies are underway to assess their benefit-risk profiles in these settings.

PMID: 29672182 [PubMed - indexed for MEDLINE]

Paroxetine and fluconazole therapy for HIV-associated neurocognitive impairment: results from a double-blind, placebo-controlled trial.

J Neurovirol. 2018 02;24(1):16-27

Authors: Sacktor N, Skolasky RL, Moxley R, Wang S, Mielke MM, Munro C, Steiner J, Nath A, Haughey N, McArthur J

Abstract
Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2 × 2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20 mg/day, (2) fluconazole 100 mg every 12 h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change = 0.25 vs - 0.19, p = 0.049), CalCAP sequential test reaction time (mean change = 0.34 vs -0.23, p = 0.014), Trail Making Part B test performance (mean change = 0.49 vs - 0.33, p = 0.041), and FAS verbal fluency (mean change = 0.25 vs 0.02, p = 0.020) but a decline in the Letter number sequencing test (mean change = - 0.40 vs 0.26, p = 0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.

PMID: 29063516 [PubMed - indexed for MEDLINE]

An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer.

Cancers (Basel). 2019 Oct 02;11(10):

Authors: Leung SW, Chou CJ, Huang TC, Yang PM

Abstract
Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients' overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients' tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

PMID: 31581665 [PubMed]