Lithium Pharmacogenetics: Where Do We Stand?

Drug Dev Res. 2016 Sep 16;

Authors: Pisanu C, Melis C, Squassina A

Abstract
Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BPD. Drug Dev Res, 2016. © 2016 Wiley Periodicals, Inc.

PMID: 27633500 [PubMed - as supplied by publisher]

A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer.

PLoS One. 2016;11(9):e0162407

Authors: Vitali F, Cohen LD, Demartini A, Amato A, Eterno V, Zambelli A, Bellazzi R

Abstract
The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our "in-silico" findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing.

PMID: 27632168 [PubMed - as supplied by publisher]

Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

PLoS Comput Biol. 2016 Sep;12(9):e1005074

Authors: Cheng F, Murray JL, Zhao J, Sheng J, Zhao Z, Rubin DH

Abstract
Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

PMID: 27632082 [PubMed - as supplied by publisher]

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells.

Oncotarget. 2016 Sep 8;

Authors: Heinrich JC, Donakonda S, Haupt VJ, Lennig P, Zhang Y, Schroeder M

Abstract
Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads - chlorpromazine - is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.

PMID: 27626687 [PubMed - as supplied by publisher]

Glutamate release inhibitor, Riluzole, inhibited proliferation of human hepatocellular carcinoma cells by elevated ROS production.

Cancer Lett. 2016 Sep 6;

Authors: Seol HS, Lee SE, Song JS, Lee HY, Park S, Kim I, Singh SR, Chang S, Jang SJ

Abstract
Liver cancer is one of the common malignancies in many countries and an increasing cause of cancer death. Despite of that, there are few therapeutic options available with inconsistent outcome, raising a need for developing alternative therapeutic options. Through a drug repositioning screening, we identified and investigated the action mechanism of the Riluzole, an amyotrophic lateral sclerosis (ALS) drug, on hepatocellular carcinoma (HCC) therapy. Treatment of the Riluzole leads to a suppression of cell proliferation in liver primary cancer cells and cancer cell lines. In addition, Riluzole induced caspase-dependent apoptosis and G2/M cell cycle arrest in SNU449 and Huh7 cell lines. In a line with the known function of glutamate release inhibitor, we found Riluzole-treated cells have increased the level of inner cellular glutamate that in turn decrease the glutathione (GSH) level and finally augment the reactive oxygen species (ROS) production. We confirm this finding in vivo by showing the Riluzole-induced GSH and ROS changes in a Huh7 xenograft cancer model. Altogether, these data suggest the anti-cancer effect of Riluzole on hepatocellular carcinoma and the suppression of glutamate signaling might be a new target pathway for HCC therapy.

PMID: 27612558 [PubMed - as supplied by publisher]

Low-dose salinomycin induces anti-leukemic responses in AML and MLL.

Oncotarget. 2016 Sep 6;

Authors: Roulston GD, Burt CL, Kettyle LM, Matchett KB, Keenan HL, Mulgrew NM, Ramsey JM, Dougan C, McKiernan J, Grishagin IV, Mills KI, Thompson A

Abstract
Development of anti-cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-cancer disease, are currently being used to identify candidates for repurposing based on their anti-cancer properties. Here, we show that low-dose salinomycin, a coccidiostat ionophore previously identified in a breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore, salinomycin treatment of primary cells resulted in loss of leukemia repopulation ability following transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and protein interactions as potential transducers of low dose salinomycin treatment. Additionally, increased protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for salinomycin in aggresome/vesicle formation indicative of an autophagic response.Together, the data support the efficacy of salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other therapies is warranted for future clinical trial.

PMID: 27612428 [PubMed - as supplied by publisher]

Highlights from the 1st Latin American meeting on metronomic chemotherapy and drug repositioning in oncology, 27-28 May, 2016, Rosario, Argentina.

Ecancermedicalscience. 2016;10:672

Authors: Rosé A, André N, Rozados VR, Mainetti LE, Márquez MM, Rico MJ, Schaiquevich P, Villarroel M, Gregianin L, Graupera JM, García WG, Epelman S, Alasino C, Alonso D, Chantada G, Scharovsky OG

Abstract
Following previous metronomic meetings in Marseille (2011), Milano (2014), and Mumbai (2016), the first Latin American metronomic meeting was held in the School of Medical Sciences, National University of Rosario, Rosario, Argentina on 27 and 28 of May, 2016. For the first time, clinicians and researchers with experience in the field of metronomics, coming from different countries in Latin America, had the opportunity of presenting and discussing their work. The talks were organised in three main sessions related to experience in the pre-clinical, and clinical (paediatric and adult) areas. The different presentations demonstrated that the fields of metronomic chemotherapy and repurposing drugs in oncology, known as metronomics, constitute a branch of cancer therapy in permanent evolution, which have strong groups working in Latin America, both in the preclinical and the clinical settings including large, adequately designed randomised studies. It was shown that metronomics offers treatments, which, whether they are combined or not with the standard therapeutic approaches, are not only effective but also minimally toxic, with the consequent improvement of the patient's quality of life, and inexpensive, a feature very important in low resource clinical settings. The potential use of metronomic chemotherapy was proposed as a cost/effective treatment in low-/middle-income countries, for adjuvant therapy in selected tumours. The fundamental role of the governmental agencies and non-governmental alliances, as the Metronomic Global Health Initiative, in supporting this research with public interest was underlined.

PMID: 27610198 [PubMed]

Repositioning of bromocriptine for treatment of acute myeloid leukemia.

J Transl Med. 2016;14:261

Authors: Lara-Castillo MC, Cornet-Masana JM, Etxabe A, Banús-Mulet A, Torrente MÁ, Nomdedeu M, Díaz-Beyá M, Esteve J, Risueño RM

Abstract
BACKGROUND: Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.
METHODS: An in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson's disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.
RESULTS: Treatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells.
CONCLUSIONS: Our results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.

PMID: 27604463 [PubMed - in process]

Multiple sclerosis: Repurposing dopaminergic drugs for MS--the evidence mounts.

Nat Rev Neurol. 2016 Apr;12(4):191-2

Authors: Marino F, Cosentino M

PMID: 27020558 [PubMed - indexed for MEDLINE]

Antileishmanial activity of ezetimibe: inhibition of sterol biosynthesis, in vitro synergy with azoles and efficacious in experimental cutaneous leishmaniasis.

Antimicrob Agents Chemother. 2016 Sep 6;

Authors: Andrade-Neto VV, Cunha-Júnior EF, Canto-Cavalheiro MM, Atella GC, Fernandes TA, Costa PR, Torres-Santos EC

Abstract
Leishmaniasis affects mainly low-income populations in tropical regions. Radical innovation in drug discovery is time- and money-consuming, causing severe restrictions to launch new chemical entities to treat neglected diseases. Drug repositioning is an attractive strategy to attend a specific demand more easily. In this project, we have evaluated the antileishmanial activity of 30 drugs currently in clinical usage for different morbidities. Ezetimibe, clinically used to reduce intestinal cholesterol absorption in dyslipidemic patients, killed promastigotes of L. amazonensis, with an IC50 of 30 μM. Morphological analysis revealed that ezetimibe caused the parasites to become rounded with multiple nuclei and flagellae. Analysis by GC/MS showed that promastigotes treated with ezetimibe had a lower amount of C14-demethylated sterols and accumulated cholesterol and lanosterol. Then, we evaluated the combination of ezetimibe with well-known antileishmanial azoles. The Fractional Inhibitory Concentration Index (FICI) indicated synergy when ezetimibe is associated with ketoconazole or miconazole. Ezetimibe activity was confirmed against intracellular amastigotes, with an IC50 of 20 μM, and reduced the IC90 of ketoconazole and miconazole from 11.3 and 11.5 μM to 4.14 and 8.25 μM, respectively. Following, ezetimibe confirmed its activity in vivo, decreasing the lesion development and parasite load in murine cutaneous leishmaniasis. We concluded that ezetimibe has promising antileishmanial activity and should be considered in association with azoles in further preclinical and clinical studies.

PMID: 27600041 [PubMed - as supplied by publisher]

Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing.

Sci Rep. 2016;6:32745

Authors: Udrescu L, Sbârcea L, Topîrceanu A, Iovanovici A, Kurunczi L, Bogdan P, Udrescu M

Abstract
Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications.

PMID: 27599720 [PubMed - in process]

New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study.

J Exp Clin Cancer Res. 2016;35(1):137

Authors: Tommasino C, Gambardella L, Buoncervello M, Griffin RJ, Golding BT, Alberton M, Macchia D, Spada M, Cerbelli B, d'Amati G, Malorni W, Gabriele L, Giammarioli AM

Abstract
BACKGROUND: The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug.
METHODS: Hence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model.
RESULTS: Low dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent.
CONCLUSIONS: Our screening approach led to the identification of a "low cost" newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations.

PMID: 27599543 [PubMed - in process]

Expression of DRD2 is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice.

Gastroenterology. 2016 Aug 28;

Authors: Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, Monast A, von Knebel Doeberitz M, Neoptolemos JP, Costello E, Greenhalf W, Scarpa A, Sipos B, Auld D, Lathrop M, Park M, Büchler MW, Strobel O, Hackert T, Giese NA, Zogopoulos G, Sangwan V, Huang S, Riazalhosseini Y, Hoheisel JD

Abstract
BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets.
METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 non-tumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference (RNAi) or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice.
RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly upregulated and 1166 genes that were significantly downregulated in PDAC, compared with non-tumor pancreatic tissues. One gene that was upregulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit alpha i2 (GNAI2), which has not been previously associated with PDAC. GNAI2 mediates the effects of dopamine receptor D2 (DRD2) on cAMP-signaling; PDAC tissues had a slight but significant increase in DRD2 mRNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNAi knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNAi knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis.
CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might tested in patients with pancreatic cancer.

PMID: 27578530 [PubMed - as supplied by publisher]

Fusing literature and full network data improves disease similarity computation.

BMC Bioinformatics. 2016;17(1):326

Authors: Li P, Nie Y, Yu J

Abstract
BACKGROUND: Identifying relatedness among diseases could help deepen understanding for the underlying pathogenic mechanisms of diseases, and facilitate drug repositioning projects. A number of methods for computing disease similarity had been developed; however, none of them were designed to utilize information of the entire protein interaction network, using instead only those interactions involving disease causing genes. Most of previously published methods required gene-disease association data, unfortunately, many diseases still have very few or no associated genes, which impeded broad adoption of those methods. In this study, we propose a new method (MedNetSim) for computing disease similarity by integrating medical literature and protein interaction network. MedNetSim consists of a network-based method (NetSim), which employs the entire protein interaction network, and a MEDLINE-based method (MedSim), which computes disease similarity by mining the biomedical literature.
RESULTS: Among function-based methods, NetSim achieved the best performance. Its average AUC (area under the receiver operating characteristic curve) reached 95.2 %. MedSim, whose performance was even comparable to some function-based methods, acquired the highest average AUC in all semantic-based methods. Integration of MedSim and NetSim (MedNetSim) further improved the average AUC to 96.4 %. We further studied the effectiveness of different data sources. It was found that quality of protein interaction data was more important than its volume. On the contrary, higher volume of gene-disease association data was more beneficial, even with a lower reliability. Utilizing higher volume of disease-related gene data further improved the average AUC of MedNetSim and NetSim to 97.5 % and 96.7 %, respectively.
CONCLUSIONS: Integrating biomedical literature and protein interaction network can be an effective way to compute disease similarity. Lacking sufficient disease-related gene data, literature-based methods such as MedSim can be a great addition to function-based algorithms. It may be beneficial to steer more resources torward studying gene-disease associations and improving the quality of protein interaction data. Disease similarities can be computed using the proposed methods at http:// www.digintelli.com:8000/ .

PMID: 27578323 [PubMed - in process]

Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity.

Antimicrob Agents Chemother. 2015 Dec;59(12):7161-9

Authors: Neville AJ, Zach SJ, Wang X, Larson JJ, Judge AK, Davis LA, Vennerstrom JL, Davis PH

Abstract
Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts.

PMID: 26392504 [PubMed - indexed for MEDLINE]

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Nat Med. 2016 Aug 29;

Authors: Xu M, Lee EM, Wen Z, Cheng Y, Huang WK, Qian X, Tcw J, Kouznetsova J, Ogden SC, Hammack C, Jacob F, Nguyen HN, Itkin M, Hanna C, Shinn P, Allen C, Michael SG, Simeonov A, Huang W, Christian KM, Goate A, Brennand KJ, Huang R, Xia M, Ming GL, Zheng W, Song H, Tang H

Abstract
In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

PMID: 27571349 [PubMed - as supplied by publisher]

Semantic Web Ontology and Data Integration: a Case Study in Aiding Psychiatric Drug Repurposing.

AMIA Jt Summits Transl Sci Proc. 2016;2016:132-9

Authors: Liang C, Sun J, Tao C

Abstract
Despite ongoing progress towards treating mental illness, there remain significant difficulties in selecting probable candidate drugs from the existing database. We describe an ontology - oriented approach aims to represent the nexus between genes, drugs, phenotypes, symptoms, and diseases from multiple information sources. Along with this approach, we report a case study in which we attempted to explore the candidate drugs that effective for both bipolar disorder and epilepsy. We constructed an ontology that incorporates the knowledge between the two diseases and performed semantic reasoning task on the ontology. The reasoning results suggested 48 candidate drugs that hold promise for a further breakthrough. The evaluation was performed and demonstrated the validity of the proposed ontology. The overarching goal of this research is to build a framework of ontology - based data integration underpinning psychiatric drug repurposing. This approach prioritizes the candidate drugs that have potential associations among genes, phenotypes and symptoms, and thus facilitates the data integration and drug repurposing in psychiatric disorders.

PMID: 27570661 [PubMed]

Explore Small Molecule-induced Genome-wide Transcriptional Profiles for Novel Inflammatory Bowel Disease Drug.

AMIA Jt Summits Transl Sci Proc. 2016;2016:22-31

Authors: Cai X, Chen Y, Gao Z, Xu R

Abstract
Inflammatory Bowel Disease (IBD) is a chronic and relapsing disorder, which affects millions people worldwide. Current drug options cannot cure the disease and may cause severe side effects. We developed a systematic framework to identify novel IBD drugs exploiting millions of genomic signatures for chemical compounds. Specifically, we searched all FDA-approved drugs for candidates that share similar genomic profiles with IBD. In the evaluation experiments, our approach ranked approved IBD drugs averagely within top 26% among 858 candidates, significantly outperforming a state-of-art genomics-based drug repositioning method (p-value < e-8). Our approach also achieved significantly higher average precision than the state-of-art approach in predicting potential IBD drugs from clinical trials (0.072 vs. 0.043, p<0.1) and off-label IBD drugs (0.198 vs. 0.138, p<0.1). Furthermore, we found evidences supporting the therapeutic potential of the top-ranked drugs, such as Naloxone, in literature and through analyzing target genes and pathways.

PMID: 27570643 [PubMed]

Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis.

Sci Rep. 2016;6:32083

Authors: Thomas SM, Purmal A, Pollastri M, Mensa-Wilmot K

Abstract
The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a "drug repurposing" approach, we tested anti-trypanosomal effects of carbazole-derived compounds called "Curaxins". In vitro screening of 26 compounds revealed 22 with nanomolar potency against axenically cultured bloodstream trypanosomes. In a murine model of HAT, oral administration of compound 1 cured the disease. These studies established 1 as a lead for development of drugs against HAT. Pharmacological time-course studies revealed the primary effect of 1 to be concurrent inhibition of mitosis coupled with aberrant licensing of S-phase entry. Consequently, polyploid trypanosomes containing 8C equivalent of DNA per nucleus and three or four kinetoplasts were produced. These effects of 1 on the trypanosome are reminiscent of "mitotic slippage" or endoreplication observed in some other eukaryotes.

PMID: 27561392 [PubMed - in process]

A genomics-based systems approach towards drug repositioning for rheumatoid arthritis.

BMC Genomics. 2016;17(Suppl 7):518

Authors: Xu R, Wang Q

Abstract
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. RA affects up to 1 % of the population worldwide. Currently, there are no drugs that can cure RA or achieve sustained remission. The unknown cause of the disease represents a significant challenge in the drug development. In this study, we address this challenge by proposing an alternative drug discovery approach that integrates and reasons over genetic interrelationships between RA and other genetic diseases as well as a large amount of higher-level drug treatment data. We first constructed a genetic disease network using disease genetics data from Genome-Wide Association Studies (GWAS). We developed a network-based ranking algorithm to prioritize diseases genetically-related to RA (RA-related diseases). We then developed a drug prioritization algorithm to reposition drugs from RA-related diseases to treat RA.
RESULTS: Our algorithm found 74 of the 80 FDA-approved RA drugs and ranked them highly (recall: 0.925, median ranking: 8.93 %), demonstrating the validity of our strategy. When compared to a study that used GWAS data to directly connect RA-associated genes to drug targets ("direct genetics-based" approach), our algorithm ("indirect genetics-based") achieved a comparable overall performance, but complementary precision and recall in retrospective validation (precision: 0.22, recall: 0.36; F1: 0.27 vs. precision: 0.74, recall: 0.16; F1: 0.28). Our approach performed significantly better in novel predictions when evaluated using 165 not-yet-FDA-approved RA drugs (precision: 0.46, recall: 0.50; F1: 0.47 vs. precision: 0.40, recall: 0.006; F1: 0.01).
CONCLUSIONS: In summary, although the fundamental pathophysiological mechanisms remain uncharacterized, our proposed computation-based drug discovery approach to analyzing genetic and treatment interrelationships among thousands of diseases and drugs can facilitate the discovery of innovative drugs for treating RA.

PMID: 27557330 [PubMed - as supplied by publisher]