Concise Review: Cell Surface N-Linked Glycoproteins as Potential Stem Cell Markers and Drug Targets.

Stem Cells Transl Med. 2016 Jul 28;

Authors: Boheler KR, Gundry RL

Abstract
: Stem cells and their derivatives hold great promise to advance regenerative medicine. Critical to the progression of this field is the identification and utilization of antibody-accessible cell-surface proteins for immunophenotyping and cell sorting-techniques essential for assessment and isolation of defined cell populations with known functional and therapeutic properties. Beyond their utility for cell identification and selection, cell-surface proteins are also major targets for pharmacological intervention. Although comprehensive cell-surface protein maps are highly valuable, they have been difficult to define until recently. In this review, we discuss the application of a contemporary targeted chemoproteomic-based technique for defining the cell-surface proteomes of stem and progenitor cells. In applying this approach to pluripotent stem cells (PSCs), these studies have improved the biological understanding of these cells, led to the enhanced use and development of antibodies suitable for immunophenotyping and sorting, and contributed to the repurposing of existing drugs without the need for high-throughput screening. The utility of this latter approach was first demonstrated with human PSCs (hPSCs) through the identification of small molecules that are selectively toxic to hPSCs and have the potential for eliminating confounding and tumorigenic cells in hPSC-derived progeny destined for research and transplantation. Overall, the cutting-edge technologies reviewed here will accelerate the development of novel cell-surface protein targets for immunophenotyping, new reagents to improve the isolation of therapeutically qualified cells, and pharmacological studies to advance the treatment of intractable diseases amenable to cell-replacement therapies.
SIGNIFICANCE: Chemoproteomic techniques that target the cell surfaceome have begun to improve cell immunophenotyping, advance antibody development and usage for sorting, and identify drug targets that advance pharmacological screening and drug repurposing. The development of these techniques and application to stem cells has the potential to accelerate efforts toward the safe use of pluripotent stem cell-derived progeny in regenerative medicine without complicating tumorigenic potential.

PMID: 27471308 [PubMed - as supplied by publisher]

[LIRAGUTIDE AT A DOSE OF 3.0 MG (SAXENDA): NEW INDICATION FOR THE TREATMENT OF OBESITY].

Rev Med Liege. 2016 May;71(5):256-61

Authors: Scheen AJ

Abstract
Liraglutide is an analogue of Glucagon-Like Peptide-1 (GLP-1) already indicated under the trade name of Victoza for the treatment of type 2 diabetes, at usual doses of 1.2 or 1.8 mg as once daily subcutaneous injection. It is henceforth indicated at a dose of 3.0 mg, also as once daily subcutaneous injection, for the treatment of obesity or overweight with comorbidities under the trade name of Saxenda, in combination with diet and exercise. Besides a specific action on the endocrine pancreas, mainly responsible for the antihyperglycaemic effect, liraglutide helps controlling appetite at the hypothamalic level. A specific programme of controlled trials (especially SCALE studies) demonstrated both efficacy and safety of the 3.0 mg dose of liraglutide in obese or overweight patients with various comorbidities.

PMID: 27337846 [PubMed - indexed for MEDLINE]

Strategies in the discovery of novel antifungal scaffolds.

Future Med Chem. 2016 Jul 27;

Authors: Liu N, Wang C, Su H, Zhang W, Sheng C

Abstract
The development of next-generation antifungal agents with novel chemical scaffolds and new mechanisms of action is vital due to increased incidence and mortality of invasive fungal infections and severe drug resistance. This review will summarize current strategies to discover novel antifungal scaffolds. In particular, high-throughput screening, drug repurposing, antifungal natural products and new antifungal targets are focused on. New scaffolds with validated antifungal activity, their discovery and optimization process as well as structure-activity relationships are discussed in detail. Perspectives that could inspire future antifungal drug discovery are provided.

PMID: 27463376 [PubMed - as supplied by publisher]

Potential Reuse of Oncology Drugs in the Treatment of Rare Diseases.

Trends Pharmacol Sci. 2016 Jul 22;

Authors: Liu Z, Fang H, Slikker W, Tong W

Abstract
Cancer research has made remarkable progress with the help of advancing genomics techniques, resulting in more precise clinical application and many new anticancer drugs on the market. By contrast, very few treatment options are available for rare diseases that are often progressive, severe, and life-threatening. In this opinion we elaborate on the possible association between cancers and rare diseases across three different levels including clinical observation, crosstalk between germline mutation and somatic mutation, and shared biological pathways. Consequently, by utilizing systematic drug-repositioning approaches, and taking safety issues into consideration, we suggest that oncology drugs have great potential for reuse in the treatment of rare diseases.

PMID: 27461952 [PubMed - as supplied by publisher]

Anti-inflammatory effects of dabrafenib on polyphosphate-mediated vascular disruption.

Chem Biol Interact. 2016 Jul 22;

Authors: Lee S, Ku SK, Bae JS

Abstract
The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Previous studies have reported polyphosphate (PolyP)-mediated vascular inflammatory responses such as disruption of vascular integrity. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. This study illustrates drug repositioning with dabrafenib (DAB) for the modulation of PolyP-mediated vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Dabrafenib suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, dabrafenib demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of dabrafenib on various systemic inflammatory diseases, such as sepsis or septic shock.

PMID: 27458080 [PubMed - as supplied by publisher]

Scoring multiple features to predict drug disease associations using information fusion and aggregation.

SAR QSAR Environ Res. 2016 Jul 25;:1-20

Authors: Moghadam H, Rahgozar M, Gharaghani S

Abstract
Prediction of drug-disease associations is one of the current fields in drug repositioning that has turned into a challenging topic in pharmaceutical science. Several available computational methods use network-based and machine learning approaches to reposition old drugs for new indications. However, they often ignore features of drugs and diseases as well as the priority and importance of each feature, relation, or interactions between features and the degree of uncertainty. When predicting unknown drug-disease interactions there are diverse data sources and multiple features available that can provide more accurate and reliable results. This information can be collectively mined using data fusion methods and aggregation operators. Therefore, we can use the feature fusion method to make high-level features. We have proposed a computational method named scored mean kernel fusion (SMKF), which uses a new method to score the average aggregation operator called scored mean. To predict novel drug indications, this method systematically combines multiple features related to drugs or diseases at two levels: the drug-drug level and the drug-disease level. The purpose of this study was to investigate the effect of drug and disease features as well as data fusion to predict drug-disease interactions. The method was validated against a well-established drug-disease gold-standard dataset. When compared with the available methods, our proposed method outperformed them and competed well in performance with area under cover (AUC) of 0.91, F-measure of 84.9% and Matthews correlation coefficient of 70.31%.

PMID: 27455069 [PubMed - as supplied by publisher]

Computational approaches for innovative antiepileptic drug discovery.

Expert Opin Drug Discov. 2016 Jul 25;

Authors: Talevi A

Abstract
INTRODUCTION: Despite the approval of a large number of antiepileptic agents over the past 25 years, there has been no significant improvement in efficacy of treatments, with one third of patients suffering from intractable epilepsy. This scenario has prompted the search for innovative drug discovery solutions. While network pharmacology and explanations of the drug resistance phenomena have been proposed to drive the search for more efficacious therapeutic solutions, such alternative approaches have not fully taken hold within the antiepileptic drug discovery community so far.
AREAS COVERED: Herein, the author discusses the impact that network pharmacology and the current hypotheses of refractory epilepsy and drug repurposing could have if integrated with anti-epileptic computer-aided discovery.
EXPERT OPINION: With many complex diseases, the advancement in the understanding of disorder pathophysiology in addition to the contribution of systems biology have rapidly translated into the discovery of novel drug candidates. However, antiepileptic drug developers have fallen a little behind in this regard, with fewer examples of computer-aided antiepileptic drug design and network-based approximations appearing in scientific literature. New generation single-target agents have so far shown limited success in terms of enhanced efficacy; although multi-target agents could yet demonstrate improved safety and efficacy.

PMID: 27454246 [PubMed - as supplied by publisher]

Getting the Most out of PubChem for Virtual Screening.

Expert Opin Drug Discov. 2016 Jul 25;

Authors: Kim S

Abstract
INTRODUCTION: With the emergence of the "big data" era, the biomedical research community has great interest in exploiting publicly available chemical information for drug discovery. PubChem is an example of public databases that provide a large amount of chemical information free of charge.
AREAS COVERED: This article provides an overview of how PubChem's data, tools, and services can be used for virtual screening and reviews recent publications that discuss important aspects of exploiting PubChem for drug discovery.
EXPERT OPINION: PubChem offers comprehensive chemical information useful for drug discovery. It also provides multiple programmatic access routes, which are essential to build automated virtual screening pipelines that exploit PubChem data. In addition, PubChemRDF allows users to download PubChem data and load them into a local computing facility, facilitating data integration between PubChem and other resources. PubChem resources have been used in many studies for developing bioactivity and toxicity prediction models, discovering polypharmacologic (multi-target) ligands, and identifying new macromolecule targets of compounds (for drug-repurposing or off-target side effect prediction). These studies demonstrate the usefulness of PubChem as a key resource for computer-aided drug discovery and related area.

PMID: 27454129 [PubMed - as supplied by publisher]

Drug screening: Drug repositioning needs a rethink.

Nature. 2016 Jul 21;535(7612):355

Authors: Ding X

PMID: 27443733 [PubMed - in process]

Prospects for Moxidectin as a New Oral Treatment for Human Scabies.

PLoS Negl Trop Dis. 2016 Mar;10(3):e0004389

Authors: Mounsey KE, Bernigaud C, Chosidow O, McCarthy JS

PMID: 26985995 [PubMed - indexed for MEDLINE]

DESM: portal for microbial knowledge exploration systems.

Nucleic Acids Res. 2016 Jan 4;44(D1):D624-33

Authors: Salhi A, Essack M, Radovanovic A, Marchand B, Bougouffa S, Antunes A, Simoes MF, Lafi FF, Motwalli OA, Bokhari A, Malas T, Amoudi SA, Othum G, Allam I, Mineta K, Gao X, Hoehndorf R, C Archer JA, Gojobori T, Bajic VB

Abstract
Microorganisms produce an enormous variety of chemical compounds. It is of general interest for microbiology and biotechnology researchers to have means to explore information about molecular and genetic basis of functioning of different microorganisms and their ability for bioproduction. To enable such exploration, we compiled 45 topic-specific knowledgebases (KBs) accessible through DESM portal (www.cbrc.kaust.edu.sa/desm). The KBs contain information derived through text-mining of PubMed information and complemented by information data-mined from various other resources (e.g. ChEBI, Entrez Gene, GO, KOBAS, KEGG, UniPathways, BioGrid). All PubMed records were indexed using 4,538,278 concepts from 29 dictionaries, with 1 638 986 records utilized in KBs. Concepts used are normalized whenever possible. Most of the KBs focus on a particular type of microbial activity, such as production of biocatalysts or nutraceuticals. Others are focused on specific categories of microorganisms, e.g. streptomyces or cyanobacteria. KBs are all structured in a uniform manner and have a standardized user interface. Information exploration is enabled through various searches. Users can explore statistically most significant concepts or pairs of concepts, generate hypotheses, create interactive networks of associated concepts and export results. We believe DESM will be a useful complement to the existing resources to benefit microbiology and biotechnology research.

PMID: 26546514 [PubMed - indexed for MEDLINE]

Explicit Drug Re-positioning: Predicting Novel Drug-Target Interactions of the Shelved Molecules with QM/MM Based Approaches.

Adv Protein Chem Struct Biol. 2015;100:89-112

Authors: Omer A, Suryanarayanan V, Selvaraj C, Singh SK, Singh P

Abstract
With the demand to enhance the speed of the drug discovery process there has been an increased usage of computational approaches in drug discovery studies. However because of their probabilistic outcomes, the challenge is to exactly mimic the natural environment which can provide the exact charge polarization effect while estimating the binding energy between protein and ligand. There has been a large number of scoring functions from simple one to the complex one available for estimating binding energy. The quantum mechanics/molecular mechanics (QM/MM) hybrid approach has been the preferred choice of interest since last decade for modeling reactions in biomolecular systems. The application of QM/MM approach has been expanded right from rescoring the already known complexes and depicting the correct position of some novel molecule to ranking a large number of molecules. It is expected that the application of QM/MM-based scoring will grow in all areas of drug discovery. However, the most promising area will be its application in repositioning, that is, assigning novel functions or targets to the already existing drugs, as this would stop the rising attrition rates as well as reduce the overall time and cost of drug discovery procedure.

PMID: 26415842 [PubMed - indexed for MEDLINE]

Tumor deconstruction as a tool for advanced drug screening and repositioning.

Pharmacol Res. 2016 Jul 15;

Authors: Naik RR, Luo T, Kohandel M, Bapat SA

Abstract
A major focus of contemporary drug screening strategies is the identification of novel anticancer compounds, which often results in underutilization of resources. Current drug evaluation involves in vivo tumor (xenograft) regression as proof-of-principle for cytotoxicity (POC). However, this end-point lacks any assessment of drug resistance of the residual tumor and its capability to establish refractory and/or recurrent disease, which would represent more appropriate indicators of therapeutic failure. We have recently developed a flow cytometry-based approach for the analyses of intra-tumor cellular heterogeneity across stem cell hierarchies, genetic instability and differential cell cycling fractions, which can potentially be predictive of refractory disease and tumor relapse. Iterating this approach after initial POC screening in the drug discovery pipeline would have a great impact in terms of precision of drug evaluation, design of optimal drug combinations and/or drug repositioning. In this perspective, we highlight how through embracing of a comprehensive, informative and analytical assessment of the cellular content of residual tumors, the fidelity and statistical robustness of preclinical drug discovery can be greatly improved.

PMID: 27431330 [PubMed - as supplied by publisher]

Repurposing old drugs to chemoprevention: the case of metformin.

Semin Oncol. 2016 Feb;43(1):123-33

Authors: Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, DeCensi A, Szabo E

Abstract
Multiple epidemiologic studies have documented an association between the anti-diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention.

PMID: 26970131 [PubMed - indexed for MEDLINE]

A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers.

Cancers (Basel). 2016;8(7)

Authors: Ahmed K, Shaw HV, Koval A, Katanaev VL

Abstract
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach. Nonsteroidal anti-inflammatory drugs like aspirin, the anti-leprotic clofazimine, and the anti-trypanosomal suramin are among examples of drugs having recently revealed WNT-targeting activities. In total, 16 human-use drug compounds have been found to be working through the WNT pathway and show promise for their prospective repositioning against various cancers. Advances, hurdles, and prospects of developing these molecules as potential drugs against WNT-dependent cancers, as well as approaches for discovering new ones for repositioning, are the foci of the current review.

PMID: 27429001 [PubMed - as supplied by publisher]

Suppressive effects of methylthiouracil on polyphosphate-mediated vascular inflammatory responses.

J Cell Mol Med. 2016 Jul 15;

Authors: Min G, Ku SK, Jeong S, Baek MC, Bae JS

Abstract
Drug repositioning is used to discover drug candidates to treat human diseases, through the application of drugs or compounds that are approved for the treatment of other diseases. This method can significantly reduce the time required and cost of discovering new drug candidates for human diseases. Previous studies have reported pro-inflammatory responses of endothelial cells to the release of polyphosphate (PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of methylthiouracil (MTU), which is an antithyroid drug, and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behaviour of human neutrophils and vascular permeability were determined in PolyP-activated HUVECs and mice. MTU suppressed the PolyP-mediated vascular barrier permeability, up-regulation of inflammatory biomarkers, adhesion/migration of leucocytes, and activation and/or production of nuclear factor-κB, tumour necrosis factor-α and interleukin-6. Furthermore, MTU demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of MTU on various systemic inflammatory diseases, such as sepsis or septic shock.

PMID: 27421058 [PubMed - as supplied by publisher]

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

FEBS Open Bio. 2016 May;6(5):442-60

Authors: Kozako T, Soeda S, Yoshimitsu M, Arima N, Kuroki A, Hirata S, Tanaka H, Imakyure O, Tone N, Honda S, Soeda S

Abstract
Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

PMID: 27419050 [PubMed]

Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case.

ChemMedChem. 2016 Jul 12;

Authors: Siragusa L, Luciani R, Borsari C, Ferrari S, Costi MP, Cruciani G, Spyrakis F

Abstract
Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off-target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets' overlap according to which pockets are clustered. Co-crystallized and known ligands can be cross-docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second-round selection. The compounds were demonstrated to be active in the low-micromolar range.

PMID: 27404817 [PubMed - as supplied by publisher]

Screening a Commercial Library of Pharmacologically Active Small Molecules Against Staphylococcus aureus Biofilms.

Antimicrob Agents Chemother. 2016 Jul 11;

Authors: Torres NS, Abercrombie JJ, Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK, Leung KP

Abstract
It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new-antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we have screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogen of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10μM, 104 drugs were found to be effective against planktonic S. aureus, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose response experiments. Finally, a subset of nine of these drug candidates was tested against pre-formed biofilms of S. aureus We found that three of these drugs, Niclosamide, Carmofur, and Auranofin, possessed antimicrobial activity against pre-formed biofilms, making them attractive candidates for repurposing as novel anti-biofilm therapies.

PMID: 27401577 [PubMed - as supplied by publisher]

Drug repurposing of minocycline against dengue virus infection.

Biochem Biophys Res Commun. 2016 Jul 7;

Authors: Leela SL, Srisawat C, Sreekanth GP, Noisakran S, Yenchitsomanus PT, Limjindaporn T

Abstract
Dengue virus infection is one of the most common arthropod-borne viral diseases. A complex interplay between host and viral factors contributes to the severity of infection. The antiviral effects of three antibiotics, lomefloxacin, netilmicin, and minocycline, were examined in this study, and minocycline was found to be a promising drug. This antiviral effect was confirmed in all four serotypes of the virus. The effects of minocycline at various stages of the viral life cycle, such as during viral RNA synthesis, intracellular envelope protein expression, and the production of infectious virions, were examined and found to be significantly reduced by minocycline treatment. Minocycline also modulated host factors, including the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). The transcription of antiviral genes, including 2'-5'-oligoadenylate synthetase 1 (OAS1), 2'-5'-oligoadenylate synthetase 3 (OAS3), and interferon α (IFNA), was upregulated by minocycline treatment. Therefore, the antiviral activity of minocycline may have a potential clinical use against Dengue virus infection.

PMID: 27396621 [PubMed - as supplied by publisher]