Old Compounds, New Uses, New Ways: Many Ways.

Assay Drug Dev Technol. 2017 12;15(8):353

Authors: Mucke H

PMID: 29235897 [PubMed - indexed for MEDLINE]

Multi-channel PINN: investigating scalable and transferable neural networks for drug discovery.

J Cheminform. 2019 Jul 09;11(1):46

Authors: Lee M, Kim H, Joe H, Kim HG

Abstract
Analysis of compound-protein interactions (CPIs) has become a crucial prerequisite for drug discovery and drug repositioning. In vitro experiments are commonly used in identifying CPIs, but it is not feasible to discover the molecular and proteomic space only through experimental approaches. Machine learning's advances in predicting CPIs have made significant contributions to drug discovery. Deep neural networks (DNNs), which have recently been applied to predict CPIs, performed better than other shallow classifiers. However, such techniques commonly require a considerable volume of dense data for each training target. Although the number of publicly available CPI data has grown rapidly, public data is still sparse and has a large number of measurement errors. In this paper, we propose a novel method, Multi-channel PINN, to fully utilize sparse data in terms of representation learning. With representation learning, Multi-channel PINN can utilize three approaches of DNNs which are a classifier, a feature extractor, and an end-to-end learner. Multi-channel PINN can be fed with both low and high levels of representations and incorporates each of them by utilizing all approaches within a single model. To fully utilize sparse public data, we additionally explore the potential of transferring representations from training tasks to test tasks. As a proof of concept, Multi-channel PINN was evaluated on fifteen combinations of feature pairs to investigate how they affect the performance in terms of highest performance, initial performance, and convergence speed. The experimental results obtained indicate that the multi-channel models using protein features performed better than single-channel models or multi-channel models using compound features. Therefore, Multi-channel PINN can be advantageous when used with appropriate representations. Additionally, we pretrained models on a training task then finetuned them on a test task to figure out whether Multi-channel PINN can capture general representations for compounds and proteins. We found that there were significant differences in performance between pretrained models and non-pretrained models.

PMID: 31289963 [PubMed]

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PIOGLITAZONE AS AN ADJUVANT OF AMPHOTERICIN B FOR THE TREATMENT OF CRYPTOCOCCOSIS.

Int J Antimicrob Agents. 2019 Jul 03;:

Authors: Ribeiro NQ, Santos APN, Emídio ECP, Costa MC, Freitas GJC, Carmo PHF, Silva MF, de Brito CB, de Souza DG, Paixão TA, Santos DA

Abstract
Approximately 180,000 people worldwide die from cryptococcosis yearly, probably due to the ineffectiveness and toxicity of current drugs available to treat the disease. Amphotericin B (AMB) is effective in killing the fungal, but has serious adverse effects linked to the excessive reactive oxygen species production that compromise renal function. Pioglitazone (PIO) is a PPARγ agonist widely repositioned as adjuvant of different drugs that cause toxic effects to the host due to its antioxidant and anti-inflammatory effects. In this study, we evaluated PIO for the treatment of cryptococcosis in combination with AMB. As a first result, PIO reduced serum creatinine and glutamic-oxalacetic transaminase (GOT) levels in mice treated with PIO+AMB. In vitro, PIO was able to control harmful oxidative bursts induced by AMB, without compromise the antifungal effect. In vivo, PIO+AMB increased the survival rate in comparison to AMB alone and improved the morbidity of the animals. PIO+AMB were more efficient than AMB alone in inhibiting fungal transmigration from the lungs to the brain and in killing yeasts that have reached the central nervous system, avoiding the establishment of meningoencephalitis. In a phagocytosis assay, PIO did not influence the engulfment and fungicidal activity of macrophages induced by AMB, but reduced the oxidative burst after the reduction of fungal burden, pointing to the control of the pathogen without leading to excessive stress that can be damaging to the host. In conclusion, PIO+AMB ameliorates cryptococcosis in murine model, indicating that it is a promising therapeutic adjuvant for combating and controlling the fungal infection.

PMID: 31279153 [PubMed - as supplied by publisher]

Synergy between Auranofin and Celecoxib against Colon Cancer In Vitro and In Vivo through a Novel Redox-Mediated Mechanism.

Cancers (Basel). 2019 Jul 03;11(7):

Authors: Han Y, Chen P, Zhang Y, Lu W, Ding W, Luo Y, Wen S, Xu R, Liu P, Huang P

Abstract
Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment.

PMID: 31277230 [PubMed]

Prospective of managing impaired brain insulin signalling in late onset Alzheimers disease with excisting diabetic drugs.

J Diabetes Metab Disord. 2019 Jun;18(1):229-242

Authors: Jojo GM, Kuppusamy G, Selvaraj K, Baruah UK

Abstract
Late onset Alzheimer's disease (AD) is the most common cause of dementia among elderly. The exact cause of the disease is until now unknown and there is no complete cure for the disease. Growing evidence suggest that AD is a metabolic disorder associated with impairment in brain insulin signalling. These findings enriched the scope for the repurposing of diabetic drugs in AD management. Even though many of these drugs are moving in a positive direction in the ongoing clinical studies, the extent of the success has seen to influence by several properties of these drugs since they were originally designed to manage the peripheral insulin resistance. In depth understandings of these properties is hence highly significant to optimise the use of diabetic drugs in the clinical management of AD; which is the primary aim of the present review article.

PMID: 31275894 [PubMed]

Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening.

Eur J Med Chem. 2019 Jun 24;179:557-566

Authors: Leroux F, Bosc D, Beghyn T, Hermant P, Warenghem S, Landry V, Pottiez V, Guillaume V, Charton J, Herledan A, Urata S, Liang W, Sheng L, Tang WJ, Deprez B, Deprez-Poulain R

Abstract
Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, β-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe its multiple roles, we ran a high-throughput drug repurposing screening. Ebselen, cefmetazole and rabeprazole were identified as reversible inhibitors of IDE. Ebselen is the most potent inhibitor (IC50(insulin) = 14 nM). The molecular mode of action of ebselen was investigated by biophysical methods. We show that ebselen induces the disorder of the IDE catalytic cleft, which significantly differs from the previously reported IDE inhibitors. IDE inhibition by ebselen can explain some of its reported activities in metabolism as well as in neuroprotection.

PMID: 31276900 [PubMed - as supplied by publisher]

[Identification of therapeutic targets and drug repurposing via gene network analysis].

Med Sci (Paris). 2019 Jun-Jul;35(6-7):515-518

Authors: Delahaye-Duriez A, Réda C, Gressens P

PMID: 31274080 [PubMed - in process]

Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis.

Sci Rep. 2017 Nov 17;7(1):15771

Authors: Shiryaev SA, Mesci P, Pinto A, Fernandes I, Sheets N, Shresta S, Farhy C, Huang CT, Strongin AY, Muotri AR, Terskikh AV

Abstract
One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission. Here, we show that interferon signalling-competent SJL mice support chronic ZIKV infection. Infected dams and sires are both able to transmit ZIKV to the offspring, making this an ideal model for in vivo validation of compounds shown to suppress ZIKV in cell culture. Administration of CQ to ZIKV-infected pregnant SJL mice during mid-late gestation significantly attenuated vertical transmission, reducing the ZIKV load in the foetal brain more than 20-fold. Given the limited side effects of CQ, its lack of contraindications in pregnant women, and its worldwide availability and low cost, we suggest that CQ could be considered for the treatment and prophylaxis of ZIKV.

PMID: 29150641 [PubMed - indexed for MEDLINE]

Screening a library of approved drugs reveals that prednisolone synergizes with pitavastatin to induce ovarian cancer cell death.

Sci Rep. 2019 Jul 03;9(1):9632

Authors: Abdullah MI, Abed MN, Khanim F, Richardson A

Abstract
The survival rate for patients with ovarian cancer has changed little in the past three decades since the introduction of platinum-based chemotherapy and new drugs are needed. Statins are drugs used for the treatment and prevention of cardiovascular diseases. Recent work from our laboratory has shown that pitavastatin has potential as a treatment for ovarian cancer if dietary geranylgeraniol is controlled. However, relatively high doses of statins are required to induce apoptosis in cancer cells, increasing the risk of myopathy, the most common adverse effect associated with statins. This makes it desirable to identify drugs which reduce the dose of pitavastatin necessary to treat cancer. A drug-repositioning strategy was employed to identify suitable candidates. Screening a custom library of 100 off-patent drugs for synergistic activity with pitavastatin identified prednisolone as the most prominent hit. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines. Prednisolone, alone or in some cases in combination with pitavastatin, reduced the expression of genes encoding enzymes in the mevalonate pathway, providing a mechanistic explanation for the synergy.

PMID: 31270377 [PubMed - in process]

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

Stem Cells Transl Med. 2017 01;6(1):131-138

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. Stem Cells Translational Medicine 2017;6:131-138.

PMID: 28170199 [PubMed - indexed for MEDLINE]

Drug Repurposing Patent Applications October-December 2018.

Assay Drug Dev Technol. 2019 Jul 03;:

Authors: Mucke HAM

PMID: 31268346 [PubMed - as supplied by publisher]

Efficacy of artemisinin-naphthoquine phosphate against Schistosoma haematobium adult flukes: dose-effect relationship and tegumental alterations.

J Helminthol. 2019 Jul;93(4):513-518

Authors: El-Beshbishi SN, El Bardicy S, Tadros M, Ayoub M, Taman A

Abstract
Schistosoma haematobium and Schistosoma mansoni infections have broadly overlapping geographical distributions. Praziquantel is the only treatment for human schistosomiasis, so drug tolerance and/or resistance are major concerns. Artemisinin-naphthoquine phosphate (CO-ArNp), an artemisinin-based combination therapy endorsed by the World Health Organization as a gold standard therapy for malaria, has also been identified as a promising treatment for S. mansoni. In this in vitro study, we tested the effect of 1-40 μg/ml CO-ArNp on S. haematobium worms, and inspected tegumental changes by using scanning electron microscopy (SEM), aiming to determine if this combination therapy has a broad-spectrum antischistosomal activity. Incubation of S. haematobium adults with 20 or 30 μg/ml CO-ArNp caused 100% mortality of worms within 72 or 48 h, respectively. SEM examination showed extensive tegumental alterations such as oedema, constriction, shortening and loss of spines, fissuring, sloughing and perforation, resulting in exposure of the underlying basal lamina, mainly in treated male schistosomes. Besides the well-established potent efficacy, bioavailability, tolerability and safety of the antimalarial artemisinin-naphthoquine phosphate combined therapy, these results may also suggest its possible utilization as a new broad-spectrum antischistosomal agent.

PMID: 29779499 [PubMed - indexed for MEDLINE]

Chemoproteomic Profiling Reveals Ethacrynic Acid Targets Adenine Nucleotide Translocases to Impair Mitochondrial Function.

Mol Pharm. 2018 06 04;15(6):2413-2422

Authors: Ye Z, Zhang X, Zhu Y, Song T, Chen X, Lei X, Wang C

Abstract
Ethacrynic acid (EA) is a diuretic drug that is widely used to treat high-blood pressure and swelling caused by congestive heart failure or kidney failure. It acts through noncovalent inhibition of the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop. Chemically, EA contains a Michael acceptor group that can react covalently with nucleophilic residues in proteins; however, the proteome reactivity of EA remains unexplored. Herein, we took a quantitative chemoproteomic approach to globally profile EA's targets in cancer cells. We discovered that EA induces impaired mitochondrial function accompanied by increased ROS production. Our profiling revealed that EA targets functional proteins on mitochondrial membranes, including adenine nucleotide translocases (ANTs). Site-specific mapping identified that EA covalently modifies a functional cysteine in ANTs, a mutation of which resulted in the rescuing effect on EA-induced mitochondrial dysfunction. The newly discovered modes of action offer valuable information to repurpose EA for cancer treatment.

PMID: 29763317 [PubMed - indexed for MEDLINE]

Drug Repurposing Patent Applications January-March 2019.

Assay Drug Dev Technol. 2019 Jul 03;:

Authors: Mucke HAM

PMID: 31264908 [PubMed - as supplied by publisher]

Old Antiprotozoal Drugs: Are They Still Viable Options for Parasitic Diseases or New Options for Other Diseases?

Curr Med Chem. 2019 Jun 28;:

Authors: Cortez-Maya S, Moreno-Herrera A, Palos I, Rivera G

Abstract
Parasitic diseases caused by helminths (ascariasis, hookworm, trichinosis, and schistosomiasis) and protozoa (Chagas, leishmaniasis, and amebiasis) are considered serious public health problems in developing countries. Additionally, there is a limited arsenal of anti-parasitic drugs in the current pipeline and growing drug resistance. Therefore, there is a clear need for the discovery and development of new compounds that can compete and replace these drugs that have been controlling parasitic infections over the last decades. However, this approach is highly resource-intensive, expensive and time-consuming. Accordingly, a drug repositioning strategy of existing drugs or drug-like molecules with known pharmacokinetics and safety profiles is alternatively being used as a fast approach for the identification of new treatments. The artemisinins, mefloquine, tribendimidine, oxantel pamoate and doxycycline for the treatment of helminths, and posaconazole and hydroxymethylnitrofurazone for the treatment of protozoa are promising candidates. Therefore, traditional antiprotozoal drugs, which were developed in some cases decades ago, are a valid solution. Herein, we review the current status of traditional anti-helminthic and anti-protozoal drugs in terms of drug targets, mode of action, doses, adverse effects, and parasite resistance to define their suitability for repurposing strategies. Current antiparasitic drugs are not only still viable for the treatment of helminth and protozoa infections but are also important candidates for new pharmacological treatments.

PMID: 31264538 [PubMed - as supplied by publisher]

What can independent research for mesothelioma achieve to treat this orphan disease?

Expert Opin Investig Drugs. 2019 Jul 01;:1-14

Authors: Guazzelli A, Meysami P, Bakker E, Bonanni E, Demonacos C, Krstic-Demonacos M, Mutti L

Abstract
Introduction: Malignant pleural mesothelioma (MPM) is a rare neoplasm with a poor prognosis, as current therapies are ineffective. Despite the increased understanding of the molecular biology of mesothelioma, there is still a lack of drugs that dramatically enhance patient survival. Area Covered: This review discusses recent and complete clinical trials supported by the NIH, other U.S. Federal agencies, universities and organizations found on clinicaltrials.gov. Firstly, chemotherapy-based trials are described, followed by immunotherapy and multitargeted therapy. Then we introduce drug repositioning and the use of drug docking as tools to find new interesting molecules. Finally, we highlight potential molecular pathways that may play a role in mesothelioma biology and therapy. Expert Opinion: Numerous biases are present in the clinical trials due to a restricted number of cases, inappropriate endpoints and inaccurate stratification of patients which delay the finding of a treatment for MPM. The most crucial issue of independent research for MPM is the lack of more substantive funding to translate these findings to the clinical setting. However, this approach is not necessarily scientific given the low mutational load of mesothelioma relative to other cancers, and therefore patients need a more solid rationale to have a good chance of successful treatment.

PMID: 31262194 [PubMed - as supplied by publisher]

Identification of Pyrvinium, an Anthelmintic Drug, as a Novel Anti-Adipogenic Compound Based on the Gene Expression Microarray and Connectivity Map.

Molecules. 2019 Jun 28;24(13):

Authors: Wang Z, Dai Z, Luo Z, Zuo C

Abstract
Obesity is a serious health problem, while the current anti-obesity drugs are not very effective. The Connectivity Map (C-Map), an in-silico drug screening approach based on gene expression profiles, has recently been indicated as a promising strategy for drug repositioning. In this study, we performed mRNA expression profile analysis using microarray technology and identified 435 differentially expressed genes (DEG) during adipogenesis in both C3H10T1/2 and 3T3-L1 cells. Then, DEG signature was uploaded into C-Map, and using pattern-matching methods we discovered that pyrvinium, a classical anthelminthic, is a novel anti-adipogenic differentiation agent. Pyrvinium suppressed adipogenic differentiation in a dose-dependent manner, as evidenced by Oil Red O staining and the mRNA levels of adipogenic markers. Furthermore, we identified that the inhibitory effect of pyrvinium was resulted primarily from the early stage of adipogenesis. Molecular studies showed that pyrvinium downregulated the expression of key transcription factors C/EBPa and PPARγ. The mRNA levels of notch target genes Hes1 and Hey1 were obviously reduced after pyrvinium treatment. Taken together, this study identified many differentially expressed genes involved in adipogenesis and demonstrated for the first time that pyrvinium is a novel anti-adipogenic compound for obesity therapy. Meanwhile, we provided a new strategy to explore potential anti-obesity drugs.

PMID: 31261664 [PubMed - in process]

Improved Prediction of Drug-Target Interactions Using Self-Paced Learning with Collaborative Matrix Factorization.

J Chem Inf Model. 2019 Jul 01;:

Authors: Xia LY, Yang ZY, Zhang H, Liang Y

Abstract
Identifying drug-target interactions(DTIs) plays an important role in the field of drug discovery, drug side-effect and drug repositioning. However, in vivo or biochemical experimental methods for identifying new DTIs are extremely expensive and time-consuming. Recently, in silico or various computational methods have been developed for DTIs prediction, such as ligand-based approaches and docking approaches, but these traditional computational methods have several limitations. This work utilizes the chemogenomic-based approaches for efficiently identifying potential DTIs candidates, namely Self-Paced Learning with Collaborative Matrix Factorization based on weighted low-rank approximation (SPLCMF) for DTIs prediction, which integrates multiple networks related to drugs and targets into regularized least squares and focuses on learning a low-dimensional vector representation of features. The SPLCMF framework can select samples from easy to complex into training by using soft weighting, which inclines to more faithfully reflect the latent importance of samples in training. Experimental results on synthetic data and five benchmark datasets show that our proposed SPLCMF outperforms other existing state-of-the-art approaches. These results indicate that our proposed SPLCMF can provide a useful tool to predict unknown DTIs, which may provide new insights into drug discovery, drug side-effect prediction and repositioning existing drug.

PMID: 31260620 [PubMed - as supplied by publisher]

Antiproliferative activity of ester derivatives of monensin A at the C-1 and C-26 positions.

Chem Biol Drug Des. 2019 Jul 01;:

Authors: Klejborowska G, Jędrzejczyk M, Stępczyńska N, Maj E, Wietrzyk J, Huczyński A

Abstract
Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity, including anticancer activity. A series of structurally diverse monensin esters including its C-1 esters (1-9), C-26-O-acetylated derivatives (10-15) and lactone (16) was synthesized and for the first time evaluated for their antiproliferative activity against four human cancer cell lines with different drug-sensitivity level. All of the MON derivatives exhibited in vitro antiproliferative activity against cancer cells at micromolar concentrations. The majority of the compounds was able to overcome the drug-resistance of LoVo/DX and MES-SA/DX5 cell lines. The most active compounds proved to be MON C-26-O-acetylated derivatives (10-15) which exhibited very good resistance index (RI) and high selectivity index (SI).

PMID: 31260603 [PubMed - as supplied by publisher]